4-aminopiperidine and their use as a medicine

ABSTRACT

A subject of the present application is new derivatives of 4-aminopiperidines of formula 
                 
 
in which R 1 , R 2  and R 3  represent various radical, and their preparation processes by synthetic methods in parallel in liquid and solid phase. These products having a good affinity with certain sub-types of somatostatin receptors, they are particularly useful for treating the pathological states or diseases in which one (or more) somatostatin receptors are involved.

This application is a 371 of PCT/FR00/03497 filed Dec. 13, 2000.

A subject of the present application is new derivatives of4-aminopiperidines and their preparation processes by synthetic methodsin parallel in liquid and solid phase. These products having a goodaffinity with certain sub-types of somatostatin receptors, they areparticularly useful for treating the pathological states or diseases inwhich one (or more) somatostatin receptors are involved.

Somatostatin (SST) is a cyclic tetradecapeptide which was isolated forthe first time from the hypothalamus as a substance which inhibits thegrowth hormone (Brazeau P. et al., Science 1973, 179, 77-79). It alsooperates as a neurotransmitter in the brain (Reisine T. et al.,Neuroscience 1995, 67, 777-790; Reisine T. et al., Endocrinology 1995,16, 427-442). Molecular cloning has allowed it to be shown that thebioactivity of somatostatin depends directly on a family of fivereceptors linked to the membrane.

The heterogeneity of the biological functions of somatostatin has led tostudies which try to identify the structure-activity relationships ofpeptide analogues on somatostatin receptors, which has led to thediscovery of 5 sub-types of receptors (Yamada et al., Proc. Natl. Acad.Sci. U.S.A, 89, 251-255, 1992; Raynor, K. et al, Mol. Pharmacol., 44,385-392, 1993). The functional roles of these receptors are currentlybeing actively studied. The affinities with different sub-types ofsomatostatin receptors have been associated with the treatment of thefollowing disorders/diseases. Activation of sub-types 2 and 5 has beenassociated with suppression of the growth hormone (GH) and moreparticularly with that of adenomas secreting GH (acromegalia) and thosesecreting hormone TSH. Activation of sub-type 2 but not sub-type 5 hasbeen associated with the treatment of adenomas secreting prolactin.Other indications associated with the activation of sub-types ofsomatostatin receptors are the recurrence of stenosis, inhibition of thesecretion of insulin and/or of glucagon and in particular diabetesmellitus, hyperlipidemia, insensiblity to insulin, Syndrome X,angiopathy, proliferative retinopathy, Dawn phenomenon and nephropathy;inhibition of the secretion of gastric acid and in particular pepticulcers, enterocutaneous and pancreaticocutaneous fistulae, irritablecolon syndrome, dumping syndrome, aqueous diarrhea syndrome, diarrheaassociated with AIDS, diarrhea induced by chemotherapy, acute or chronicpancreatitis and secretory gastrointestinal tumors; the treatment ofcancer such as hepatomas; the inhibition of angiogenesis, the treatmentof inflammatory disorders such as arthritis; chronic rejection ofallografts; angioplasty; the prevention of bleeding of grafted vesselsand gastrointestinal bleeding. The agonists of somatostatin can also beused to reduce the weight of a patient.

Among the pathological disorders associated with somatostatin (Moreau J.P. et al., Life Sciences 1987, 40, 419; Harris A. G. et al., TheEuropean Journal of Medicine, 1993, 2, 97-105), there can be mentionedfor example: acromegalia, hypophyseal adenomas, Cushing's disease,gonadotrophinomas and prolactinomas, catabolic side-effects ofglucocorticoids, insulin dependent diabetes, diabetic retinopathy,diabetic nephropathy, hyperthyroidism, gigantism, endocrinicgastroenteropancreatic tumors including carcinoid syndrome, VIPoma,insulinoma, nesidioblastoma, hyperinsulinemia, glucagonoma, gastrinomaand Zollinger-Ellison's syndrome, GRFoma as well as acute bleeding ofthe esophageal varices, gastroesophageal reflux, gastroduodenal reflux,pancreatitis, enterocutaneous and pancreatic fistulae but alsodiarrheas, refractory diarrheas of acquired immunodeficiency syndrome,chronic secretary diarrhea, diarrhea associated with irritable bowelsyndrome, disorders linked with gastrin releasing peptide, secondarypathologies with intestinal grafts, portal hypertension as well ashemorrhages of the varices in patients with cirrhosis, gastro-intestinalhemorrhage, hemorrhage of the gastroduodenal ulcer, Crohn's disease,systemic scleroses, dumping syndrome, small intestine syndrome,hypotension, scleroderma and medullar thyroid carcinoma, illnesseslinked with cell hyperproliferation such as cancers and moreparticularly breast cancer, prostate cancer, thyroid cancer as well aspancreatic cancer and colorectal cancer, fibroses and more particularlyfibrosis of the kidney, fibrosis of the liver, fibrosis of the lung,fibrosis of the skin, also fibrosis of the central nervous system aswell as that of the nose and fibrosis induced by chemotherapy, and othertherapeutic fields such as, for example, cephaleas including cephaleaassociated with hypophyseal tumors, pain, panic attacks, chemotherapy,cicatrization of wounds, renal insufficiency resulting from delayeddevelopment, obesity and delayed development linked with obesity,delayed uterine development, dysplasia of the skeleton, Noonan'ssyndrome, sleep apnea syndrome, Graves' disease, polycystic disease ofthe ovaries, pancreatic pseudocysts and ascites, leukemia, meningioma,cancerous cachexia, inhibition of H pylori, psoriasis, as well asAlzheimer's disease. Osteoporisis can also be mentioned.

The applicants found that the compounds of general formula describedhereafter have an affinity and a selectivity for the somatostatinreceptors. As somatostatin and its peptide analogues often have a poorbioavailability by oral route and a low selectivity (Robinson, C., Drugsof the Future, 1994, 19, 992; Reubi, J. C. et al., TIPS, 1995, 16, 110),said compounds, non-peptide agonists or antagonists of somatostatin, canbe advantageously used to treat pathological states or illnesses aspresented above and in which one (or more) somatostatin receptors areinvolved. Preferably, said compounds can be used for the treatment ofacromegalia, hypophyseal adenomas or endocrine gastroenteropancreatictumors including carcinoid syndrome.

Therefore a subject of the present invention is the compounds of generalformula

in racemic, enantiomeric form or all combinations of these forms, inwhich:

-   R₁ represents a linear or branched (C₁-C₁₆)alkyl, alkenyl, alkynyl,    —(CH₂)_(m)—Y-Z₁₁ or —(CH₂)_(m)-Z₁₂ radical in which    -   Z₁₁ represents a (C₁-C₆)alkyl or aryl optionally substituted,    -   Z₁₂ represents cyano, cyclohexenyl, bis-phenyl,        (C₃-C₇)cycloalkyl, optionally substituted (C₃-C₇)        heterocycloalkyl, optionally substituted aryl or optionally        substituted heteroaryl,    -   or Z₁₂ represents a radical of formula        or R₁ represents a radical of formula-   R₂ represents a radical of formula —C(Y)NHX₁, —C(O)X₂ or SO₂X₃;-   R₃ represents the hydrogen atom, an optionally substituted alkyl,    alkenyl, alkynyl, optionally substituted aralkyl, optionally    substituted heteroarylalkyl radical, or a radical of formula    —C(Y)—NHX₁, —(CH₂)_(n)—C(O)X₂, SO₂X₃ or-   X₁ represents a linear or branched (C₁-C₁₅)alkyl, alkenyl, alkynyl,    —(CH₂)_(m)—Y-Z₂₁ or —(CH₂)_(p)Z₂₂ radical in which    -   Z₂₁ represents a (C₁-C₆)alkyl    -   Z₂₂ represents cyclohexenyl, indanyl, bis-phenyl,        (C₃-C₇)cycloalkyl, (C₃-C₇)heterocycloalkyl, mono- or        di-alkylamino, —C(O)—O-alkyl, or aryl or heteroaryl optionally        substituted,    -   or Z₂₂ represents a radical of formula-   X₂ represents a linear or branched (C₁-C₁₀)alkyl radical, an alkenyl    radical optionally substituted by a phenyl radical (the phenyl    radical being itself optionally substituted), an alkynyl radical, or    a radical of formula —(CH₂)_(m)-W-(CH₂)_(q)-Z₂₃ or —(CH₂)_(p)-U-Z₂₄    in which    -   Z₂₃ represents a (C₁-C₆)alkyl or aryl optionally substituted;    -   Z₂₄ represents alkyl, cyclohexenyl, bis-phenyl,        (C₃-C₇)cycloalkyl optionally substituted,        (C₃-C₇)heterocycloalkyl, cyano, amino, mono or di-alkylamino, or        aryl or heteroaryl optionally substituted,    -   or Z₂₄ represents a radical of formula        or X₂ represents a radical represented below:        where the protective group (PG) represents H or        tert-butyloxycarbonyl;-   X₃ represents a linear or branched (C₁-C₁₀)alkyl radical, an alkenyl    radical optionally substituted by a phenyl radical (the phenyl    radical being itself optionally substituted), CF₃, or —(CH₂)_(p)Z₂₅    in which    -   Z₂₅ represents aryl or heteroaryl optionally substituted,        or X₃ represents a radical of formula        Optionally substituted by one or more halo radicals identical or        different;-   Y represents an oxygen or sulphur atom;-   W represents an oxygen or sulphur atom, or SO₂;-   U represents a covalent bond or the oxygen atom;-   n is an integer from 0 to 4;-   m is an integer from 1 to 6;-   p is an integer from 0 to 6;-   q is an integer from 0 to 2,-   or their addition salts with pharmaceutically acceptable mineral or    organic acids, with the exclusion of compounds of general formula I    wherein R₁ represents the radical alkyle, alkenyle or benzyle, R₂ an    optionally substituted benzyloxy and R₃ aralkyle.

A more particularly subject of the invention is the products of generalformula I as defined above, characterized in that

-   i) the substituent or substituents which can be carried by the aryl    radicals represented by Z₁₁ and Z₁₂ and heteroaryl represented by    Z₁₂ are chosen independently from the fluoro, chloro, bromo, iodo,    alkyl, alkoxy, alkylthio, —CF₃, —OCF₃, phenyl, phenoxy,    aminosulphonyl radicals;-   ii) the substituent or substituents which can be carried by the    heterocycloalkyl radical represented by Z₁₂ are chosen independently    from the oxy and alkyl radicals;-   iii) the substituent or substituents which can be carried by the    aryl and heteroaryl radicals represented by Z₂₂ are chosen    independently from the fluoro, chloro, bromo, iodo, alkyl, alkenyl,    alkoxy, alkylthio, CF₃, OCF₃, nitro, cyano, azido, aminosulphonyl,    piperidinosulphonyl, mono- or di-alkylamino, —C(O)—O-alkyl,    —C(O)-alkyl, or phenyl, phenoxy, phenylthio, benzyloxy radicals, the    phenyl radical being able to be substituted;-   iv) the substituent or substituents which can be carried by the aryl    radicals represented by Z₂₃ and Z₂₄, cycloalkyl and heteroaryl    represented by Z₂₄ are chosen independently from the fluoro, chloro,    bromo, iodo, alkyl, alkoxy, alkylthio, CF₃, OCF₃, OCHF₂, SCF₃,    nitro, cyano, azido, hydroxy, —C(O)O-alkyl, —O—C(O)-alkyl,    —NH—C(O)-alkyl, alkylsulphonyl, mono- or di-alkylamino, amino,    aminoalkyl, pyrrolyl, pyrrolydinyl or the radicals phenyl, phenoxy,    phenylthio, benzyl, benzyloxy radicals the aryl radical of which is    optionally substituted by one or more alkyl, CF₃ or halo radicals;-   v) the substituent or substituents which can be carried by the aryl    and heteroaryl radicals represented by Z₂₅ are chosen independently    from the fluoro, chloro, bromo, iodo, alkyl, alkoxy, CF₃, OCF₃,    nitro, cyano, —NH—C(O)-alkyl, alkylsulphonyl, amino, mono- and    di-alkylamino, phenyl, pyridino radicals;-   vi) the substituent which can be carried by the alkyl radical    represented by R₃ is the cyano radical;-   vii) the substituent or substituents which can be carried by the    aralkyl radical represented by R₃ are chosen independently from the    fluoro, chloro, bromo, iodo, alkyl, alkoxy, CF₃, OCF₃, OCHF₂, SCF₃,    SCHF₂, nitro, cyano, —C(O)O-alkyl, alkylsulphonyl, thiadiazolyl    radicals, or the phenyl and phenoxy radicals the phenyl radical of    which is optionally substituted by one or more halo radicals;-   viii) the substituent or substituents which can be carried by the    heteroarylalkyl radical represented by R₃ are chosen independently    from the fluoro, chloro, bromo or nitro radicals.

In the definitions indicated above, the expression halo represents thefluoro, chloro, bromo or iodo radical, preferably chloro, fluoro orbromo. The expression alkyl (when it is not specified otherwise),preferably represents a linear or branched alkyl radical having 1 to 6carbon atoms, such as the methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl and tert-butyl, pentyl or amyl, isopentyl,neopentyl, hexyl or isohexyl radicals. Among the alkyl radicalscontaining 1 to 15 carbon atoms, there can be mentioned the alkyls asdefined above but also the heptyl, octyl, nonyl, decyl, dodecyl,tridecyl or pentadecyl radicals.

By alkenyl, when it is not specified otherwise, is understood a linearor branched alkyl radical containing 1 to 6 carbon atoms and having atleast one unsaturation (double bond), such as for example vinyl, allyl,propenyl, butenyl or pentenyl. By alkynyl, when it is not specifiedotherwise, is understood a linear or branched alkyl radical containing 1to 6 carbon atoms and having at least one double unsaturation (triplebond) such as for example an ethynyl, propargyl, butynyl or pentynylradical.

The term cycloalkyl designates a monocyclic carbon system comprising 3to 7 carbon atoms, and preferably the cyclopropyl, cyclobutyl,cyclopentyl or cyclohexyl rings. The expression heterocycloalkyldesignates a saturated cycloalkyl containing 2 to 7 carbon atoms and atleast one heteroatom. This radical can contain several identical ordifferent heteroatoms. Preferably, the heteroatoms are chosen fromoxygen, sulphur or nitrogen. As examples of a heterocycloalkyl, therecan be mentioned the pyrrolidine, pyrrolidinone, imidazolidine,pyrrazolidine, isothiazolidine. thiazolidine, isoxazolidine, piperidine,piperazine or morpholine ring.

The alkoxy radicals can correspond to the alkyl radicals indicated abovesuch as for example the methoxy, ethoxy, propyloxy or isopropyloxyradicals but also linear, secondary or tertiary butoxy, pentyloxy. Theterm lower alkylthio preferably designates the radicals in which thealkyl radical is as defined above such as for example methylthio,ethylthio, The term alkylsulphonyl preferably designates the radicals inwhich the alkyl radical is as defined above.

The expression aryl represents an aromatic radical, constituted by acondensed ring or rings, such as for example the phenyl or naphthylradical. The expression heteroaryl designates an aromatic radical,constituted by a ring or condensed rings, with at least one ringcontaining one or more identical or different heteroatoms chosen fromsulphur, nitrogen or oxygen. As an example of a heteroaryl radical,there can be mentioned the thienyl, furyl, pyrrolyl, imidazolyl,pyrazolyl, isothiazolyl, thiazolyl, isoxazolyl, oxazolyl, triazolyl,pyridyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, quinoxalinyl,benzothienyl, benzofuryl, indolyl, benzoxadiazoyl radicals.

The terms mono- and di-alkylamino preferably designate the radicals inwhich the alkyl radicals are as defined above, such as for examplemethylamino, ethylamino, dimethylamino, diethylamino or(methyl)(ethyl)amino.

The symbol ->* corresponds to the attachment point of the radical. Whenthe attachment site is not specified on the radical, this signifies thatthe attachment is carried out on one of the sites which are available tothis radical for such an attachment.

A more particular subject of the present invention is the compounds ofgeneral formula I as defined above in which:

-   R₁ represents a linear or branched (C₁-C₆)alkyl radical, the    —(CH₂)_(m)—Y-Z₁₁ or —(CH₂)_(m)-Z₁₂ radical in which    -   Z₁₁ represents a (C₁-C₆)alkyl,    -   Z₁₂ represents bis-phenyl, (C₃-C₇)cycloalkyl,        (C₃-C₇)heterocycloalkyl optionally substituted, or aryl or        heteroaryl optionally substituted by one or more substituents        chosen independently from the fluoro, chloro, bromo, iodo,        alkyl, alkoxy radicals,    -   or Z₁₂ represents    -   Y represents the oxygen atom,        or R₁ represents a radical of formula-   R₂ represents a radical of formula —C(Y)NHX₁, —C(O)X₂ or SO₂X₃ in    which-   X₁ represents a linear or branched (C₁-C₁₅)alkyl radical, or    —(CH₂)_(p)Z₂₂ in which    -   -   Z₂₂ represents cyclohexenyl, bis-phenyl, (C₃-C₇)cycloalkyl,            (C₃-C₇)heterocycloalkyl, mono- or di-alkylamino,            —C(O)—O-alkyl, or aryl or heteroaryl optionally substituted            by one or more radicals chosen independently from the            fluoro, chloro, bromo, iodo, alkyl, alkoxy, alkylthio, CF₃,            OCF₃, nitro, cyano, azido, piperidinosulphonyl,            —C(O)—O-alkyl, —C(O)-alkyl, or phenyl radicals,        -   or Z₂₂ represents a radical of formula

    -   X₂ represents a linear or branched (C₁-C₁₀)alkyl, alkynyl,        —(CH₂)_(m)-W-(CH₂)_(q)-Z₂₃ or —(CH₂)_(p)-U-Z₂₄ radical in which        -   W represents SO₂,        -   U represents a covalent bond,        -   Z₂₃ represents an aryl radical;        -   Z₂₄ represents cyclohexenyl, bis-phenyl, (C₃-C₇)cycloalkyl            optionally substituted by an aminoalkyl, or aryl or            heteroaryl radical optionally substituted by one or more            radicals chosen from fluoro, chloro, bromo, iodo, alkyl,            alkoxy, —CF₃, —OCF₃, SCF₃, hydroxy, —O—C(O)-alkyl, mono- or            di-alkylamino, amino        -   or Z₂₄ represents a radical of formula

    -   or X₂ represents

    -   X₃ represents a —(CH₂)_(p)Z₂₅ radical in which Z₂₅ represents an        aryl radical optionally substituted by one or more identical or        different radicals chosen from alkoxy and CF₃,-   R₃ represents the hydrogen atom, an alkyl, alkenyl, heteroarylalkyl    radical optionally substituted or a radical of formula —C(Y)—NHX₁,    —C(O)X₂ or SO₂X₃ in which    -   X₁ represents a —(CH₂)_(p)Z₂₂ radical in which        -   Z₂₂ represents an aryl radical optionally substituted by one            or more radicals chosen independently from the fluoro,            chloro, bromo, iodo, alkyl, alkoxy, CF₃, nitro, phenoxy            radicals;    -   X₂ represents the vinyl radical substituted by a phenyl, the        phenyl radical being itself optionally substituted by one or        more halo, or —(CH₂)_(p)-U-Z₂₄ radicals in which        -   Z₂₄ represents alkyl, (C₃-C₇)cycloalkyl,            (C₃-C₇)heterocycloalkyl, bis-phenyl, amino, mono or            di-alkylamino, or aryl or heteroaryl optionally substituted            by one or more radicals chosen from alkoxy, bromo, chloro,            fluoro, hydroxy, CF₃, nitro, amino, mono- and di-alkylamino,            pyrrolyl,    -   or X₂ represents a radical of formula    -   X₃ represents a linear or branched (C₁-C₁₀)alkyl radical, the        vinyl radical substituted by a radical (the phenyl radical being        itself optionally substituted), CF₃, or —(CH₂)_(p)Z₂₅ in which        -   Z₂₅ represents aryl or heteroaryl optionally substituted by            one or more substituents chosen independently from the            fluoro, chloro, bromo, iodo, alkyl, alkoxy, CF₃, nitro,            —NH—C(O)-alkyl, mono- and di-alkylamino radicals.

Preferentially, R₁ represents a linear or branched (C₁-C₆)alkyl radical,the —(CH₂)_(m)—Y-Z₁₁ or —(CH₂)_(m)-Z₁₂ radical in which

-   -   Z₁₁ represents a (C₁-C₆)alkyl,    -   Z₁₂ represents naphthyl, morpholino, bis-phenyl, pyrrolidinyl        substituted by the oxy radical, or the phenyl, piperazinyl,        pyridinyl and indolyl radicals which are optionally substituted        by one or more substituents chosen independently from the bromo,        fluoro, chloro, alkyl, alkoxy, —CF₄, —OCF₃ radicals;    -   or Z₁₂ represents    -   Y represents the oxygen atom,        or R₁ represents a radical of formula given below:

Preferentially, R₂ represents a radical of formula —C(Y)NHX₁, —C(O)X₂ orSO₂X₃ in which

-   -   X₁ represents a linear or branched (C₁-C₁₀)alkyl, or        —(CH₂)_(p)Z₂₂ radical in which        -   Z₂₂ represents cyclohexyl, cyclohexenyl, bis-phenyl,            morpholino, piperidino, mono- or di-alkylamino,            —C(O)—O-alkyl, or phenyl, naphthyl or furyl optionally            substituted by one or more radicals chosen independently            from the fluoro, chloro, bromo, iodo, alkyl, alkoxy,            alkylthio, CF₃, OCF₃, nitro, cyano, azido,            piperidinosulphonyl, —C(O)—O-alkyl, —C(O)-alkyl or phenyl            radicals,        -   or Z₂₂ represents a radical of formula    -   X₂ represents an alkyl, alkynyl, —(CH₂)_(m)-W-(CH₂)_(q)-Z₂₃ or        —(CH₂)_(p)Z₂₄ radical in which        -   W represents SO₂;        -   Z₂₃ represents the phenyl radical;        -   Z₂₄ represents cyclohexenyl, bis-phenyl, cyclohexyl            optionally substituted by an aminoalkyl, or phenyl,            naphthyl, benzothienyl, thienyl or indolyl radical            optionally substituted by one or more radicals chosen from            fluoro, chloro, bromo, iodo, alkyl, alkoxy, —CF₃, —OCF₃,            SCF₃, hydroxy, —O—C(O)-alkyl, —NH—C(O)-alkyl, mono- or            di-alkylamino, amino, or        -   Z₂₄ represents a radical of formula            or X₂ represents    -   X₃ represents a —(CH₂)_(p)Z₂₅ radical in which Z₂₅ represents        the phenyl radical optionally substituted by one or more        identical or different radicals chosen from alkoxy and CF₃,

Preferentially, R₃ represents the hydrogen atom, an alkyl, alkenyl orfuryl-methyl radical substituted by one or more nitro radicals, or aradical of formula —C(Y)—NHX₁, —C(O)X₂ or SO₂X₃ in which

-   -   X₁ represents a —(CH₂)_(p)Z₂₂ radical in which        -   Z₂₂ represents the phenyl or naphthyl radical optionally            substituted by one or more radicals chosen independently            from the fluoro, chloro, bromo, iodo, alkyl, alkoxy, CF₃,            nitro, phenoxy radicals,    -   X₂ represents the vinyl radical substituted by a phenyl radical        itself optionally substituted by one or more halo, or        —(CH₂)_(p)-U-Z₂₄ radicals in which        -   Z₂₄ represents alkyl, cyclohexyl, tetrahydrofuryl,            bis-phenyl, amino, mono or di-alkylamino, or phenyl,            indolyl, thienyl, pyridinyl, benzothienyl and furyl            optionally substituted by one or more radicals chosen from            alkoxy, bromo, chloro, fluoro, amino, mono- and            di-alkylamino, nitro, hydroxy, pyrrolyl    -   or X₂ represents a radical of formula    -   X₃ represents a linear or branched (C₁-C₁₀)alkyl radical, the        vinyl radical substituted by a phenyl, CF₃, or —(CH₂)_(p)Z₂₅        radical in which        -   Z₂₅ represents a phenyl, naphthyl, thienyl, pyrazolyl or            thiazolyl radical optionally substituted by one or more            substituents chosen independently from the fluoro, chloro,            bromo, iodo, alkyl, alkoxy, CF₃, nitro, —NH—C(O)-alkyl,            mono- and di-alkylamino radicals;

Very preferentially, R₁ represents the —(CH₂)_(m)Z₁₂ radical in whichm=2 and Z₁₂ represents bis-phenyl or the radical indolyl substituted byone or more substituents chosen independently from the alkyl and alkoxyradicals.

Very preferentially, R₂ represents the radicals of formula —C(Y)NHX₁ and—C(O)X₂ in which

-   -   Y represents S;    -   X₁ represents a phenyl radical optionally substituted by one or        more azido radicals,    -   X₂ represents —(CH₂)_(p)Z₂₄ in which        -   p is equal to 1, 2 or 3,        -   Z₂₄ represents cyclohexyl, or phenyl or benzothienyl            optionally substituted by one or more radicals chosen from            fluoro, chloro, bromo, iodo or —CF₃.

Very preferentially, R₃ represents the hydrogen atom or the methylradical.

The compounds according to the invention can be prepared in solid orliquid phase.

A) Syntheses in Liquid Phase Via the N-substituted Piperidone

A1) Reducing Amination

It is carried out according to the following stage:

in which R represents methyl or Boc and R₁ has the meaning indicatedabove.

The general procedure is as follows: the reducing amination(Abdel-Magid, A. F.; Maryanoff, C. A.; Carson, K. G. Tetrahedron Lett.1990, 31, 5595-5598; Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.;Maryanoff, C. A.; Shah, R. D., J. Org. Chem. 1996, 61, 3849-3862) of theN-substituted piperidone is carried out in anhydrous chlorinatedsolvents such as dichloroethane in the presence of a primary amine (1.1to 1.5 eq.), a reducing agent such as sodium triacetoxyborohydride (1.1to 1.5 eq.) and acetic acid (10% by mass relative to the N-substitutedpiperidone). The reaction mixture is agitated for 1 to 4 hours atambient temperature. In certain cases, a solution of soda (0.1 M) isadded and the mixture is agitated for 20 to 90 minutes. If not, thereaction mixture is washed with a saturated solution of sodiumbicarbonate, with sodium chloride, dried over magnesium sulphate,filtered and concentrated. The desired product is purified by flashchromatography on silica gel.Preparation 1: tert-butyl 4-[(3,3-diphenylpropyl)amino]-1-piperidinecarboxylate(C₂₅H₃₄N₂O₂, M=394.56)

3,3-diphenylpropylamine (5.8 g, 27.5 mmol), sodium triacetoxyborohydride(6.36 g, 30 mmol) and 0.5 ml of acetic acid are added to 5 g (25 mmol)of N-Boc-piperidone in 100 ml of dry dichloroethane. The turbid yellowsolution is agitated at ambient temperature after 1 hour. 50 ml of asoda solution (0.1 M) is then added and the mixture is agitated for 30minutes. The organic phase is washed with a saturated solution of sodiumbicarbonate, with sodium chloride, dried over magnesium sulphate,filtered and concentrated in order to produce 10 g of a yellow solid.This solid is purified by flash chromatography on silica gel elutingwith a heptane/ethyl acetate mixture (4/1, 3/1, 2/1 then 1/1) then withpure ethyl acetate. The fractions are concentrated under vacuum in orderto produce 5.6 g (yield=57%) of a pale yellow solid.

NMR ¹H (CD₃OD, 400 MHz) δ: 7.27 (m, 8H); 7.16 (m, 2H); 4 (dd, J=6.4 and14 Hz, 3H); 2.73 (m, 2H); 2.55 (m, 3H); 2.26 (q, J=7.6 Hz, 2H); 1.78 (d,J=12 Hz, 2H); 1.45 (s, 9H); 1.15 (qd, J=4.4 and 12.8 Hz, 2H). MS/LC:m/z=395.2 (M+H).

A series of 4-aminosubstituted-1-piperidine was prepared according tothis procedure with the following other R₁ groups:

A2) Functionalization of PiperidinesA2a) Syntheses of Ureas and Thioureas

The syntheses of ureas and thioureas are implemented according to theprocedure described in the literature (Kaldor, S. W.; Siegel, M. G;Fritz, J. E.; Dressman. B. A.; Hahn, P. J. Tetrahedron Lett. 1996, 37,7193-7196; Kaldor, S. W.; Fritz, J. E.; Tang, J.; McKinney, E. R.Bioorg. Med. Chem. Lett. 1996, 6, 3041-3044; Booth, R. J.; Hodges, J. C.J Am. Chem. Soc. 1997, 119, 4882-4886; Flynn, D. L.; Crich, J. Z.;Devraj, R. V.; Hockerman, S. L.; Parlow, J. J.; South, M. S.; Woodard,S.; J. Am. Chem. Soc. 1997, 119, 4874-4881) following the followingdiagram:

in which R represents methyl or Boc and X₁ and Y have the meaningindicated above. It should be noted that in the case where R representsBoc, the product thus obtained is a final product corresponding toformula I according to the invention but can also be used as a synthesisintermediate.

The general procedure is as follows: the isocyanate or theisothiocyanate (1.1 to 1.5 eq.) is added to the4-aminosubstituted-1-piperidine in aprotic solvents such asdichloromethane, tetrahydrofuran or dimethylformamide and the mixture isagitated for 45 minutes to 18 hours at ambient temperature. Theaminomethyl resin (Novabiochem, 1.33 mmol/g, 0.2 to 1 eq.) is added andthe mixture is agitated for 45 minutes to 18 hours. In certain cases,the basic ion exchange resin such as IRA-68 (Gayo, L. M.; Suto, M. J.Tetrahedron Lett. 1997, 38, 513-516) can be added.

The resins are filtered and the filtrate is concentrated. Otherpurifications on silica gel or basic alumina cartridges (500 mg,Interchim) can optionally be carried out.

EXAMPLE A2Atert-butyl-4-((3,3-diphenylpropyl){[3-(trifluoromethyl)anilino]carbonyl}amino)-1-piperidinecarboxylate (C₃₃H₃₈F₃N₃O₃, M=581.68)

246 mg (1.32 mmol) of 3-(trifluoromethyl)phenyl isocyanate is added to asolution of tert-butyl 4-[(3,3-diphenylpropyl)amino]-1-piperidinecarboxylate (470 mg, 1.2 mmol) in 5 ml of dichloromethane. The solutionis agitated for 45 minutes, and the aminomethyl resin (180 mg, 0.36mmol) is added and the reaction medium is again placed on an orbitalshaker for 45 minutes. The resin is filtered and washed withdichloromethane. The filtrate is concentrated in vacuo in order toproduce 610 mg (yield=87%) of a white foam.

NMR ¹H (CD₃OD, 400 MHz) δ: 7.71 (s, 1H); 7.57 (d, 1H); 7.43 (t, 1H);7.26 (m, 10H); 7.15 (m, 1H); 4.1 (m, 3H); 3.97 (dd, J=7.6 and 10 Hz,1H); 3.17 (m, 2H); 2.75 (m, 2H); 2.35 (m, 2H); 1.65 (d, J=12 Hz, 2H);1.46 (s, 9H, tbutyl group); 1.39 (dd, J=2.4 and 10.8 Hz, 2H); 1.29 (s,1H). MS/LC: m/z=582 (M+H).

For the R₁ groups as illustrated in point A1 above, the X₁ groups whichcan be envisaged for the synthesis of ureas (Y=O) according to the aboveprocedure, are the following:

For the R₁ groups as illustrated in point A1 above, the X₁ groups whichcan be envisaged for the synthesis of thioureas (Y=S) according to theabove procedure, are the following:

A2b) Synthesis of Amides from Carboxylic Acids

The syntheses of amides from carboxylic acids are implemented accordingto the following reaction diagram:

in which R represents methyl or Boc and X₂ has the meaning indicatedabove. It should be noted that in the case where R represents Boc, theproduct thus obtained is a final product corresponding to formula Iaccording to the invention but can also be used such as a synthesisintermediate.

The general procedure is as follows: carboxylic acid (1.1 to 2.5 eq.)dissolved in an anhydrous aprotic solvent such as dichloromethane,dimethylformamide or tetrahydrofuran is activated with1-ethyl-3-(3-dimethylaminopropyl)carbodiimide bonded on resin (P-EDC,Novabiochem, 2.33 mmol/g, 1.3 to 3 eq.) (Desai, M. C.; StephensStramiello, L. M. Tetrahedron Lett. 1993, 34, 7685-7688). This mixtureis agitated for 5 to 30 minutes at ambient temperature.4-aminosubstituted-1-piperidine dissolved beforehand in an anhydrousaprotic solvent such as dichloromethane, dimethylformamide ortetrahydrofuran is then added and the reaction mixture is agitated atambient temperature for 1 to 18 hours. In certain cases, basic ionexchange resin (IRA-68, SAX) is added and the mixture is again agitatedat ambient temperature for 1 to 18 hours. The resins are filtered onfrit or on a basic ion exchange resin cartridge (IRA-68, SAX) or on analumina cartridge (500 mg, Interchim).

EXAMPLE A2b tert-butyl4-{(3,4-dimethoxyphenethyl)[2-(1H-indol-3-yl)acetyl]amino}-1-piperidinecarboxylate (C₃₅H₄₁N₃O₃, M=551.74)

512 mg (1.12 mmol, 1.4 eq.) of P-EDC resin is preswollen indichloromethane. 2-(1H)-indol-3-yl)acetic acid (153 mg, 0.875 mmol, 1.1eq.) is added and the mixture is agitated for 10 minutes. Tert-butyl4-[(3,3-diphenylpropyl)amino]-1-piperidine carboxylate (292 mg, 0.8mmol) in tetrahydrofuran is added and the reaction medium is agitatedovernight. 2 spatulas of basic ion exchange resin IRA-68 are added andthe reaction medium is again agitated overnight. The resins are filteredand the filtrate is concentrated under vacuum in order to produce 250 mg(yield=86%) of a pale yellow foam.

NMR ¹H (CD₃OD, 400 MHz) 67 : 7.63 (d, J=8 Hz, 1H); 7.44 (d, J=8 Hz, 1H);7.36 (d, J=8 Hz, 1H); 7.26 (d, J=8 Hz, 1H); 7.2 (m, 6H); 7.13 (m, 3H);7.1 (m, 2H); 6.68 (s, 1H); 4-3.75 (m, 4H); 3.65 (s, 1H); 3.2 (m, 1H); 3(m, 1H), 2.75 (m, 1H); 2.26 (m, 3H); 1.6 (m, 2H); 1.44 (s, 9H); 1.13 (m,2H). MS/LC: m/z=552.4 (M+H).

A series of amides was synthesized according to this procedure. The X₂radicals which can be envisaged are the following:

where the protective group (PG) represents H or tert-butyloxycarbonyl.A3) Syntheses of 4-aminodisubstituted Piperidines

The synthesis of 4-aminodisubstitueted piperidines according to theinvention, can be carried out by acid treatment of the N-Boc compoundsdescribed previously, following the following reaction diagram:

General procedure: two methods were used to carry out the deprotectionin acid media of the ureas, thioureas and amides described previously.The first consists in dissolving the compound in dichloromethane andadding trifluoroacetic acid (5 to 20 eq.) whilst in the second asolution of dilute hydrochloric acid in solvents such as ethyl acetate,dioxane or diethylether (5 to 20 eq.) is used. The reaction medium isagitated for 1 to 4 hours at ambient temperature. In certain cases,dichloromethane is added and the organic phase is washed with asaturated solution of sodium bicarbonate, dried over magnesium sulphate,filtered and concentrated under vacuum in order to isolate the freebase.

EXAMPLE A3N-(3,3-diphenylpropyl)-N-(4-piperidinyl)-N′-[3-(trifluoromethyl)phenyl]urea(C₂₈H₃₀F₃N₃₀, M=481.57)

1.6 ml (21 mmol, 20 eq.) of trifluoroacetic acid is added to a solutionof tert-butyl4-((3,3-diphenylpropyl){[3-(trifluoromethyl)anilino]carbonyl}amino)-1-piperidinecarboxylate (600 mg, 1.04 mmol) in dichloromethane. The reaction mediumis agitated for 90 minutes then concentrated. Dichloromethane is addedand the organic phase is washed with a saturated solution of sodiumbicarbonate, dried over magnesium sulphate, filtered and concentratedunder vacuum in order to isolate 490 mg (yield=98%) of a white foam.

NMR ¹H (CD₃OD, 400 MHz) δ: 7.7 (s, 1H); 7.55 (d, 1H); 7.44 (t, 1H); 7.28(m, 9H); 7.18 (m, 2H); 4.05 (m, 2H); 3.26 (m, 2H); 3.11 (d, J=10.8 Hz,2H); 2.7 (td, J=2.4 and 12.4 Hz, 2H); 2.38 (q, J=8 Hz, 2H); 1.76 (d,J=10 Hz, 2H); 1.63 (qd, J=4 and 12.4 Hz, 2H). MS/LC: m/z=482.2 (M+H).

A series of 4-aminopiperidines was synthesized according to thisprocedure. The R₁, X₁ and X₂ radicals which can be envisaged are thosealready illustrated in points A1 and A2 above.

B) Syntheses in Solid Phase of 4-aminopiperidines

4-aminopiperidines were prepared by synthesis in solid phase startingwith Wang resin.

B1) Preparation of the Resin

B1a) Preparation of the p-nitrophenyl Carbonate Wang Resin

It is carried out according to the following diagram

This resin was prepared from Wang resin (supplied by Bachem orNovabiochem) with a load rate greater than 0.89 mmol/g, following theprocedure described in the literature (Bunin, B. A. The CombinatorialIndex, Academic Press, 1998, p. 62-63; Dressman, B. A.; Spangle, L. A.;Kaldor, S. W. Tetrahedron Lett. 1996, 37,;937-940; Hauske, J. R.; Dorff,P. Tetrahedron Lett. 1995, 36, 1589-1592; Cao, J.; Cuny, G. D.; Hauske,J. R. Molecular Diversity 1998, 3, 173-179): N-methylmorpholine orpyridine and 4-nitrophenyl chloroformate are added successively to theWang resin preswollen in dichloromethane or tetrahydrofuran at ambienttemperature. The mixture is agitated overnight. The resin is washed withtetrahydrofuran, with diethylether and with dichloromethane then driedin vacuo at 50° C. overnight.

B1b) Preparation of the Piperidone Carbamate Resin

It is carried out according to the following diagram

Triethylamine (1 eq.) and the molecular sieve are added to the hydratedpiperidone hydrochloride diluted in dimethylformamide. The mixture isheated until complete dissolution of the ketone. This solution is addedto the p-nitrophenyl carbonate Wang resin (0.05 eq.) preswollen indimethylformamide. After agitation for 24 to 72 hours at ambienttemperature, the resin is filtered then washed several times withdimethylformamide, tetrahydrofuran, diethylether and dichloromethane.

Preparation 2

2.5 g of p-nitrophenyl carbonate Wang resin (load rate of 0.88 mmol/g,2.2 mmol) is preswollen in 100 ml of dimethylformamide. At the sametime, 6.7 g (44 mmol, 20 eq.) of hydrated piperidone hydrochloride, 4.45g (44 mmol, 20 eq.) of triethylamine and three spatulas of molecularsieve are heated in 100 ml of dimethylformamide until completedissolution. The yellowish solution is poured warm onto the resin andthe mixture is agitated for 40 hours at ambient temperature. The resinis filtered then washed with dimethylformamide, tetrahydrofuran,diethylether and dichloromethane (3 times with each solvent) then driedunder vacuum. 2.4 g of pale yellow resin is isolated with a load rate of0.88 mmol/g calculated after elementary analysis of the nitrogen.

B2) Reducing Amination on Solid Support

It is carried out according to the diagram

The general procedure is the following: the primary amine (5 to 10 eq.)is added to the ketonic resin preswollen in trimethylorthoformate (TMOF)then the mixture is sonicated. Then, the borane pyridine complex (8M, 5to 10 eq.) is added and the mixture is agitated for 12 to 72 hours. Theresin is filtered, washed with solvents such as dichloromethane,dimethylformamide and tetrahydrofuran then dried under vacuum (Pelter,A.; Rosser, R. M. J. Chem. Soc. Perkin Trans I 1984, 717-720; Bomann, M.D.; Guch, I. C.; DiMare, M. J. Org. Chem. 1995, 60, 5995-5996; Khan, N.M.; Arumugam, V.; Balasubramanian, S. Tetrahedron Lett. 1996, 37,4819-4822).Preparation 3

300 mg (load rate of 0.88 mmol/g, 0.27 mmol) of ketonic resin ispreswollen in TMOF. Then 4-bromophenethylamine (540 mg, 420 μl, 2.7mmol, 10 eq.) then the borane pyridine complex (8 M, 338 μl, 2.7 mmol,10 eq.) are added. The mixture is agitated for 56 hours at ambienttemperature. The resin is filtered, rinsed successively withdichloromethane, dimethylformamide, tetrahydrofuran and dichloromethanethen dried under vacuum. 340 mg of pale yellow resin is thus obtainedwith a load rate of 0.81 mmol/g calculated after elementary analysis ofthe nitrogen.

B3) Functionalization

B3a) Functionalization with Isocyanates or Isothiocyanates

It is carried out according to the diagram

The general procedure is the following: the “secondary amine” resin ispreswollen in a solvent such as dichloromethane or dimethylformamidebefore the addition of isocyanate or isothiocyanate (3 to 10 eq.). Themixture is agitated for 1 to 24 hours at ambient temperature. The resinis then filtered, washed with solvents such as dichloromethane,dimethylformamide and tetrahydrofuran then dried under vacuum. Cleavageof the resin is carried out in the presence of an equimolar mixture ofdichloromethane and trifluoroacetic acid and agitation is carried outfor 30 minutes to 4 hours. The resin is rinsed with dichloromethane thenthe filtrate is concentrated under vacuum. In certain cases the filtrateis redissolved in dichloromethane then desalified with a saturatedsolution of sodium carbonate. The organic phase is evaporated undervacuum in order to produce the free base.

EXAMPLE B3aN-(4-bromophenethyl)-N-(4-piperidinyl)-N′-[4-(trifluoromethyl)phenyl]urea(C₂₁H₂₃BrF₃N₃O, M=470.3)

55 mg (50 μmol) of resin (see Preparation 3) is preswollen in anhydrousdichloromethane. Then 4-trifluorophenylisocyanate (28 mg, 150 μmol, 3eq.) is added and the whole is agitated overnight. The resin isfiltered, rinsed with tetrahydrofuran, with dimethylformamide, withtetrahydrofuran then with dichloromethane before being dried undervacuum. Then agitation is carried out for 1.5 hour in the presence of800 μl of an equimolar mixture of dichloromethane and trifluoroaceticacid. The resin is filtered and rinsed with dichloromethane, thefiltrate is concentrated, rediluted in dichloromethane and washed with asaturated solution of sodium bicarbonate. 6 mg of a brown oil(yield=25%) is thus isolated.

NMR ¹H (CD₃OD, 400 MHz) δ: 7.53 (m, 4H); 7.44 (d, J=6.8 Hz, 2H); 7.21(d, J=8.4 Hz, 2H); 4.1 (m, 1H); 3.53 (t, J=7.2 Hz, 2H); 3.12 (d, J=12.8Hz, 2H); 2.89 (t, J=8 Hz, 2H); 2.7 (m, 2H); 1.73 (m, 4H). MS/LC:m/z=472.2 (M+H).

A series of ureas (Y=O) and thioureas (Y=S) was synthesized according tothis procedure. The R₁ radicals which can be envisaged are thefollowing:

The X₁ radicals which can be envisaged are those illustrated in point Aabove.

B3b) Functionalization with Sulphonyl Chlorides

It is carried out according to the following diagram

General procedure: the “secondary amine” resin is preswollen in solventssuch as dichloromethane, dimethylformamide or tetrahydrofuran. Thensulphonyl chloride (5 to 10 eq.) and triethylamine (6 to 12 eq.) areadded and the mixture is agitated for 12 to 24 hours at ambienttemperature. The resin is filtered, washed with solvents such asdichloromethane, dimethylformamide and tetrahydrofuran, then dried undervacuum. Then the resin is agitated for 1 to 4 hours in the presence ofan equimolar mixture of dichloromethane and trifluoroacetic acid. Theresin is rinsed with dichloromethane then the filtrate is concentratedunder vacuum. In certain cases the filtrate is redissolved indichloromethane then desalified with a saturated solution of sodiumcarbonate. The organic phase is evaporated under vacuum in order toproduce the free base.

EXAMPLE B3b N-(4-bromophenethyl)-4-methoxy-N-(4-piperidinyl)phenylsulphonamide (C₂₀H₂₅BrN₂O₃S, M=453.4)

55 mg (50 μmol) of resin (see Preparation 3) is preswollen in anhydrousdichloromethane. Then triethylamine (42 μl, 300 μmol, 6 eq.) then4-methoxybenzene sulphonyl chloride (51.5 mg, 250 μmol, 5 eq.) are addedand the whole is agitated overnight. The resin is filtered, rinsed withtetrahydrofuran, with dimethylformamide, with tetrahydrofuran then withdichloromethane before being dried under vacuum. The reaction isrepeated a second time in order to have a complete substitution. 800 μlof an equimolar mixture of dichloromethane and trifluoroacetic acid isadded and agitation is carried out for 1.5 hour at ambient temperature.The resin is filtered and rinsed with dichloromethane. The filtrate isconcentrated, rediluted in dichloromethane and washed with a saturatedsolution of sodium bicarbonate. 14 mg of a brown oil (yield=63%) werethus isolated.

NMR ¹H (CD₃OD, 400 MHz) δ: 7.8 (dd, J=2.8 and 10 Hz, 2H); 7.44 (dd,J=1.2 and 6.8 Hz, 2H); 7.17 (d, J=8.4 Hz, 2H); 7.07 (dd, J=3.2 and 10Hz,2H); 3.87 (s, 3H, OCH₃); 3.72 (m, 1H); 3.3 (m, 2H); 3.04 (d, J=12.8 Hz,2H); 2.92 (t, J=8.4 Hz, 2H); 2.6 (t, J=12.4 Hz, 2H); 1.58 (m, 2H); 1.47(broad d, J=10 Hz, 2H). MS/LC: m/z=455 (M+H).

A series of sulphonamides was synthesized according to this procedure.The R₁ radicals which can be envisaged are those illustrated in points Aand B3a above. The X₃ radicals which can be envisaged are the following:

B3c) Functionalization with Acid Chlorides

It is carried out according to the following diagram

General procedure: the “secondary amine” resin is preswollen in solventssuch as dichloromethane, dimethylformamide or tetrahydrofuran. Then theacid chloride (5 to 10 eq.) and triethylamine (6 to 12 eq.) are addedand the mixture is agitated for 12 to 24 hours at ambient temperature.The resin is filtered, washed with solvents such as dichloromethane,dimethylformamide and tetrahydrofuran, then dried under vacuum. Theresin is then agitated for 1 to 4 hours in the presence of an equimolarmixture of dichloromethane and trifluoroacetic acid. The resin is rinsedwith dichloromethane then the filtrate is concentrated under vacuum. Incertain cases the filtrate is redissolved in dichloromethane thendesalified with a saturated solution of sodium carbonate. The organicphase is evaporated under vacuum in order to produce the free base.

EXAMPLE B33c N-(4-bromophenethyl)-N-(4-piperidinyl)-2-thiophenecarboxamide (C₁₈H₂₁BrN₂OS, M=393.3)

55 mg (50 μl) of resin (see Preparation 3) is preswollen in anhydroustetrahydrofuran. Then triethylamine (42 μl, 300 μmol, 6 eq.) then2-thiophene carbonyl chloride (37 mg, 250 μmol, 5 eq.) are added and thewhole is agitated overnight. The resin is filtered, rinsed withtetrahydrofuran, with dimethylformamide. with tetrahydrofuran then withdichloromethane before being dried under vacuum. 800 μl of an equimolarmixture of dichloromethane and trifluoroacetic acid is added andagitation is carried out for 1.5 hour at ambient temperature. The resinis filtered and rinsed with dichloromethane. The filtrate isconcentrated, rediluted in dichloromethane and washed with a saturatedsolution of sodium bicarbonate in order to obtain 10 mg of a brown oil(yield=50%).

NMR ¹H (CD₃OD, 400 MHz) δ: 7.64 (dd, J=0.8 and 4.8 Hz, 1H); 7.44 (d,J=8.4 Hz, 2H); 7.36 (d, J=3.6 Hz, 1H); 7.14 (m, 3H); 4.11 (m, 1H); 3.61(t, J=8 Hz, 2H)); 3.09 (d, J=12Hz, 2H); 2.92 (m, 2H); 2.54 (mn, 2H);1.82 (m, 2H); 1.7 (m, 2H). MS/LC: m/z=393.1 (M+H).

A series of amides was synthesized according to this procedure. The R₁groups envisaged are those illustrated in points A and B3 above. The X₂groups are illustrated below.

B3d) Functionalization with Carboxylic Acids

It is carried out according to the procedure described in the literature(Kobayashi, S; Aoki, Y., J. Comb. Chem. 1999, 1, 371-372) following thediagram:

General procedure: the “secondary amine” resin is preswollen in solventssuch as dichloromethane, dimethylformamide or tetrahydrofuran. Then thecarboxylic acid (3 to 5 eq.), benzo-triazol-1-yl-oxy-tris-pyrrolidinophosphonium hexafluorophosphate (PyBoP, 3 to 5 eq.) anddiisopropylethylamine (6 to 10 eq.) are added and the mixture isagitated for 24 hours at ambient temperature. The resin is filtered,washed with solvents such as dichloromethane, dimethylformamide andtetrahydrofuran, then dried under vacuum. Then the resin is agitated for1 to 4 hours in the presence of an equimolar mixture of dichloromethaneand trifluoroacetic acid. The resin is rinsed with dichloromethane thenthe filtrate is concentrated under vacuum. In certain cases the filtrateis redissolved in dichloromethane then desalified with a saturatedsolution of sodium carbonate. The organic phase is evaporated undervacuum in order to produce the free base.

EXAMPLE B3d N-[2-(4-bromophenyl)ethyl]-N-(4-piperidinyl)acetamide(C₁₅H₂₁BrN₂O, M=325.25)

55 mg (50 μmol) of resin (see Preparation 3) is preswollen in anhydrousdimethylformamide. Then acetic acid (8.8 mg, 150 μmol, 3 eq.) PyBoP (76mg, 150 μmol, 3 eq.) then diisopropylethylamine (38 mg, 300 μmol, 6 eq.)are added and the whole is agitated overnight. The resin is filtered,rinsed with dimethylformamide, with tetrahydrofuran then withdichloromethane before being dried under vacuum. 800 μl of an equimolarmixture of dichloromethane and trifluoroacetic acid is added andagitation is carried out for 1.5 hour at ambient temperature. The resinis filtered and rinsed with dichloromethane. The filtrate isconcentrated, rediluted in dichloromethane and washed with a saturatedsolution of sodium bicarbonate in order to obtain 11 mg of a brown oil(yield=68%).

NMR ¹H (CD₃OD, 400 MHz) δ: 7.44 (m, 2H); 7.20 (m, 2H); 4.05 (m, 1H);3.45 (m, 2H); 3.10 (m, 2H); 2.83 (m, 2H); 2.64 (m, 2H); 2.13 (s,3H);1.73 (m, 4H). MS/LC: m/z=325.2 (M+H).

A series of amides was synthesized according to this procedure. The R₁groups envisaged are those illustrated in points A and B3a above. The X₂groups are illustrated in point A above.

C) Functionalization of the Piperidine Part in Solution

C1) Obtaining Piperidine with R₃=—C(Y)NHX₁

It is carried out according to the diagram

General procedure: an isocyanate or isothiocyanate (1.1 to 1.5 eq.) isadded to piperidine in the form of the free base diluted indichloromethane. The mixture is agitated for one to 18 hours at ambienttemperature. The aminomethyl resin (0.2 to 1 eq.) is added and themixture is again agitated for 2 to 18 hours. In certain cases, ionexchange resin such as IRA68 or SAX is added. The resins are filteredand the filtrate is concentrated. In certain cases, the product isdissolved in dichloromethane or ethyl acetate then filtered on a silicagel or basic alumina cartridge (500 mg, Interchim).

EXAMPLE C14-((3,3-diphenylpropyl){[3-(trifluoromethyl)anilino]carbonyl}amino)-N-phenyl-1-piperidinecarboxamide (C₃₅H₃₅F₃N₄O₂, M=600.68)

N-(3,3-diphenylpropyl)-N-(4-piperidinyl)-N′-[3-(trifluoromethyl)phenyl]urea(24 mg, 0.05 mmol) is dissolved in dichloromethane. Phenylisocyanate (9mg, 0.075 mmol, 1.5 eq.) is added and the mixture is agitated for 2.5hours. The aminomethyl resin (0.02 mmol) is added and the reaction isagain agitated overnight. The resin is filtered, rinsed withdichloromethane and the filtrate is concentrated. The oil obtained ispassed through a silica gel cartridge eluting with an equimolar mixtureof heptane and ethyl acetate in order to obtain 12 mg (yield=40%) of ayellow oil after concentration.

NMR ¹H (CD₃OD, 400 MHz) δ: 7.72 (s, 1H); 7.58 (d, 1H); 7.44 (m, 1H);7.38 (m, 2H); 7.29 (m, 12H); 7.12 (m, 2H); 7.07 (m, 1H); 4.2 (d,J=12.4Hz, 3H); 3.21 (t, J=8 Hz, 2H); 2.9 (t, J=12.4 Hz, 2H); 2.38 (q,J=8 Hz, 2H); 1.73 (d, J=10 Hz, 2H); 1.54 (qd, J=3.6 and 12 Hz, 2H).MS/LC: m/z=601.4 (M+H).

A series of ureas (Y=O) and thioureas (Y=S) was synthesized according tothis procedure. The R₁, X₁ and X₂ groups which can be envisaged, arethose illustrated in the above points (A and B3a), A, and (A and B3c)respectively.

C2) Functionalization with Carboxylic Acids

It is carried out according to the following diagram

General procedure: the P-EDC resin (1.3 to 3 eq.) is preswollen inanhydrous dichloromethane. Carboxylic acid (1.1 to 2.5 eq.) is dissolvedin an anhydrous solvent such as dichloromethane, dimethylformamide ortetrahydrofuran and is added to the resin. This mixture is agitated for5 to 30 minutes at ambient temperature. The 4-aminodisubstitutedpiperidine, in the form of the free base, in solution in an anhydroussolvent such as dichloromethane, dimethylformamide or tetrahydrofuran isthen added to this mixture and the whole is agitated for 1 to 18 hoursat ambient temperature. In certain cases, ion exchange resin such asIRA68 or SAX is added and the mixture is again agitated at ambienttemperature for 1 to 18 hours. The resins are filtered on frit, on a SAXion exchange resin cartridge (500 mg, Interchim) or on a basic aluminacartridge (500 mg, Interchim).

EXAMPLE C2N-(1-acetyl-4-piperidinyl)-N-(3,3-diphenylpropyl)-N′-[3-(trifluoromethyl)phenyl]urea(C₃₀H₃₂F₃N₃O₂, M=523.60)

117 mg (175 μmol, 3.5 eq.) of P-EDC resin is preswollen in 1.5 ml ofanhydrous dichloromethane. Acetic acid (7.5 mg, 125 μmol, 2.5 eq.) isadded and the mixture is agitated for 10 minutes. ThenN-(3,3-diphenylpropyl)-N-(4-piperidinyl)-N′-[3-(trifluoromethyl)phenyl]urea(24.3 mg, 50 μmol) is added in its turn and the mixture is agitatedovernight. The resin is filtered and the filtrate is concentrated. Theoil obtained is passed through a silica gel cartridge eluting with anequimolar mixture of heptane and ethyl acetate in order to obtain 16 mg(yield=62%) of a white foam after concentration.

NMR ¹H (CD₃OD, 400 MHz) δ: 7.71 (s, 1H); 7.58 (d, J=8.4 Hz, 1H); 7.43(t, J=8 Hz, 1H); 7.28 (m, 9H); 7.17 (m, 2H); 4.56 (dd, J=2 and 11.2 Hz,1H); 4.17 (m, 1H); 3.96 (t, J=7.6 Hz, 1H); 3.88 (d, J=12 Hz, 1H); 3.19(q, J=4 and 8 Hz, 2H); 3.1 (t, J=12 Hz, 1H); 2.58 (t, J=12 Hz, 1H); 2.37(m, 2H); 2.06 (s, 3H, CH₃); 1.72 (t, J=14.4 Hz, 2H); 1.43 (qd, J=4 and12.4 Hz, 2H). MS/LC: m/z=524.3 (M+H).

A series of amides was synthesized according to this procedure. The R₁,X₁ and X₂ groups which can be envisaged, are those illustrated in points(A and B3a), A, (A and B3c) respectively.

C3) Functionalization with Sulphonyl Chlorides

It is carried out according to the following diagram

General procedure: the morpholinomethyl resin (Novabiochem, 2 to 3 eq.)is preswollen in anhydrous solvents such as dichloromethane,dimethylformamide or tetrahydrofuran. Sulphonyl chloride (1.1 to 2 eq.)dissolved in anhydrous solvents such as dichloromethane,dimethylformamide or tetrahydrofuran is added, followed by4-aminodisubstituted piperidine. The mixture is agitated for 16 to 48hours. The aminomethyl resin (0.1 to 1.5 eq.) is added and the reactionmedium is agitated overnight. In certain cases, ion exchange resin suchas IRA68 or SAX is added and the mixture is agitated at ambienttemperature for 1 to 18 hours. The resins are filtered on frit, on a SAXion exchange resin cartridge (500 mg, Interchim) or on a basic aluminacartridge (500 mg, Interchim).

EXAMPLE C3N-(3,3-diphenylpropyl)-N-{1-[(4-methoxyphenyl)sulphonyl]-4-piperidinyl}-N′-[3-(trifluoromethyl)phenyl]urea(C₃₅H₃₆F₃N₃O₄S, M=651.75)

27.5 mg (100 μmol, 2 eq.) of morpholinomethyl resin is preswollen inanhydrous tetrahydrofuran, then 4-methoxyphenylsulphonyl chloride (15.5mg, 0.075 mmol, 1.5 eq.) thenN-(3,3-diphenylpropyl)-N-(4-piperidinyl)-N′-[3-(trifluoromethyl)phenyl]urea(24.3 mg, 0.05 mmol) are added. The mixture is agitated overnight. Theaminomethyl (20 mg) and SAX ion exchange resins are added and themixture is agitated overnight. The resins are filtered and rinsed withdichloromethane. The oil obtained after evaporation is passed through asilica gel cartridge (500 mg, Interchim) eluting with ethyl acetate inorder to obtain 18 mg (yield=56%) of a white solid after concentration.

NMR ¹H (CD₃OD, 400 MHz) δ: 7.71 (d, J=9.2 Hz, 2H); 7.65 (s, 1H); 7.51(d, 1H); 7.41 (t, J=7.6 Hz, 1H); 7.29 (m, 9H); 7.20 (m, 2H); 7.11 (dd,J=1.6 and 6.8 Hz, 2H); 3.88 (s, 31H, OCH₃); 3.77 (d, J=12.4 Hz, 2H);3.16 (t, J=8 Hz, 2H); 2.33 (m, 4H): 1.71 (d, J=10 Hz, 2H); 1.62 (qd, J=4and 12 Hz, 2H); 1.3 (m, 2H). MS/LC: m/z=652.4 (M+H).

A series of sulphonamides was synthesized according to this procedure.The R₁, X₁, X₂ and X₃ groups which can be envisaged are thoseillustrated in points (A and B3a), A, (A and B3c) and B3b respectively.

D) Synthesis of Tri-substituted Piperidines in Solid Phase

It is carried out starting from vinyl sulphone resin (Kroll, F. E. K.;Morphy, R.; Rees, D.: Gani. I) Tetrahedron Lett. 1997, 38, 8573-8576;Brown, A. R. J. Comb. Chem. 1999, 1, 283-285) according to the followingdiagram:

D1) Preparation of the Resin

It is carried out according to the following diagram:

Triethylamine (1 eq.) is added to hydrated piperidone hydrochloridediluted in dimethylformamide. The mixture is heated until completedissolution of the ketone. This solution is added to the vinyl sulphoneresin (0.05 eq.) preswollen in dimethylformamide. After agitation for 24to 72 hours at ambient temperature, the resin is filtered then washedseveral times with dimethylformamide, tetrahydrofuran, diethylether anddichloromethane.

Preparation 4

1.5 g of vinyl sulphone resin (Novabiochem, load rate of 1 mmol/g, 1.5mmol) is preswollen in 50 ml of dimethylformamide. At the same time, 2.3g (15 mmol, 10 eq.) of hydrated piperidone hydrochloride and 1.8 g (15mmol, 10 eq.) of triethylamine are heated in 100 ml of dimethylformamideuntil complete dissolution. The yellowish solution is poured warm ontothe resin and the mixture is agitated for 24 hours at ambienttemperature. The resin is filtered then washed with dimethylformamide,tetrahydrofuran, diethylether and dichloromethane (3 times with eachsolvent) then dried under vacuum. 1.7 g of pale yellow resin is isolatedwith a load rate of 1 mmol/g calculated after elementary analysis of thenitrogen.

D2) Reducing Amination on Solid Support

It is carried out according to the procedure described in the literature(Pelter, A.; Rosser, R. M.; J. Chem. Soc. Perkin Trans I 1984, 717-720;Bomann, M. D.; Guch, I. C.; DiMare, M.; J. Org. Chem. 1995, 60,5995-5996; Khan, N. M.; Arumugam, V.; Balasubramanian, S.; TetrahedronLett. 1996, 37, 4819-4822) following the diagram:

General procedure: The primary amine (5 to 10 eq.) is added to theketonic resin preswollen in trimethylorthoformate (TMOF) then themixture is sonicated. Then the borane pyridine complex (8 M, 5 to 10eq.) is added and the mixture is agitated for 12 to 72 hours. The resinis filtered, washed with solvents such as dichloromethane,dimethylformamide, methanol and tetrahydrofuran then dried under vacuum.Preparation 5

1 g (load rate of 1 mmol/g, 1 mmol) of ketonic resin is preswollen inTMOF. Then 2-(1-methyl-1H)-indol-3-yl)ethylamine (1.01 g, 10 mmol, 10eq.) then the borane pyridine complex (8M, 1.25 ml, 10 mmol, 10 eq.) areadded. The mixture is agitated for 48 hours at ambient temperature. Theresin is filtered, rinsed successively with dichloromethane,dimethylformamide, methanol, tetrahydrofuran and dichloromethane thendried under vacuum. 1.05 g of pale yellow resin is thus obtained with aload rate of 0.91 mmol/g calculated after elementary analysis of thenitrogen.

D3) Functionalization of the Secondary Amine

D3a) Functionalization with Isocyanates

General procedure: the “secondary amine” resin is preswollen in asolvent such as dichloromethane or dimethylformamide before the additionof isocyanate (3 to 10 eq.). The mixture is agitated for 1 to 24 hoursat ambient temperature. The resin is then filtered, washed with solventssuch as dichloromethane, dimethylformamide and tetrahydrofuran thendried under vacuum.Preparation 6

55 mg (50 μmol) of resin (see Preparation 5) is preswollen in anhydrousdichloromethane. Then 4-trifluorophenylisocyanate (28 mg, 150 μmol, 3eq.) is added and the whole is agitated for 2 hours at ambienttemperature. The resin is filtered, rinsed with tetrahydrofuran, withdimethylformamide, with tetrahydrofuran then with dichloromethane beforebeing dried under vacuum.

D3b) Functionalization with Sulphonyl Chlorides

The Functionalization operating method is identical to that stated inpoint B3b.

D3c) Functionalization with Acid Chlorides

The functionalization operating method is identical to that stated inpoint B3c.

D3d) Functionalization with Carboxylic Acids

The functionalization operating method is identical to that stated inpoint B3d.

D4) Cleavage Stage

The cleavage stage described below is valid whatever thefunctionalization carried out beforehand on the secondary amine:

General procedure: The disubstituted resin is swollen in solvents suchas dichloromethane, dimethylformamide or tetrahydrofuran then the halideR₃X is added in which R₃ has the meaning indicated previously and Xrepresents a halogen atom (5 eq.) and the mixture agitated overnight ata temperature comprised between 20 and 60° C. The resin is filtered,rinsed with solvents such as dimethylformamide, tetrahydrofuran,methanol and dichloromethane then dried under vacuum. The resin isswollen again in dichloromethane and basic ion exchange resin (Ouyang,X.; Armstrong, R. W.; Murphy, M. M. J. Org. Chem. 1998, 63, 1027-1032)is added. The whole is agitated for 48 hours at ambient temperature. Theresins are filtered, rinsed with dichloromethane and the filtrate isconcentrated under vacuum.

EXAMPLE D4N-[2-(1-methyl-1H-indol-3-yl)ethyl]-N-(1-methyl-4-piperidinyl)-N′-[4-(trifluoromethyl)phenyl]urea(C₂₅H₂₉F₃N₄O, M=458.5)

55 mg (50 μmol) of the urea resin is swollen in dimethylformamide then35 mg (250 μmol, 5 eq.) of iodomethane is added and the mixture isagitated for 18 hours at ambient temperature. The resin is filtered,rinsed with dimethylformamide, tetrahydrofuran, methanol anddichloromethane then dried under vacuum. The resin is swollen again indichloromethane then approximately 100 mg of amberlite IRA68 resin isadded and the mixture is agitated for 48 hours. The resins are filtered,rinsed with dichloromethane and the filtrate is concentrated in order toproduce 18 mg (yield=78%) of a colourless oil.

NMR ¹H (CD₃OD, 400 MHz) δ: 7.65 (m, 2H); 7.40 (m, 2H); 7.31 (m, 1H);7.20 (t, 1H); 7.10 (m, 1H); 7.06 (m, 2H); 4.04 (m, 1H); 3.68 (s, 3H);3.60 (t, 2H); 3.04 (t, 2); 2.94 (m, 2H); 2.29 (s, 3H); 2.14 (m, 2H);1.91 (m, 2H); 1.76 (m, 2H). MS/LC: m/z=459.3 (M+H).

For the R₁, X₁, X₂ and X₃ groups as illustrated in points A and B above,the R₃ groups which can be envisaged for the synthesis of trisubstituted4-aminopiperidines according to the above procedure, are the following:

A subject of the invention is also the process for the preparation ofcompounds I according to the invention, in solid or liquid phase, asdescribed previously.

A more particular subject of the invention is a process for thepreparation, in liquid phase, of compounds of formula I as definedabove, characterized in that it comprises the reducing amination of thefollowing N-substituted piperidone

in which R represents the methyl or Boc radical, in the presence of anamine of formula R₁NH₂ in which R₁ has the meaning indicated above, inorder to obtain the compound of formula 1

which compound of formula (1) is reacted with

-   A) either a compound of formula X₁NC(Y) in which X₁ and Y have the    meaning indicated above, in order to obtain a compound of formula    (2)    which compound of formula (2) represents the corresponding compound    of formula (I) in which R₃ represents Me or Boc and which, when R₃    represents Boc, can be subjected to an acid treatment in order to    obtain the corresponding compound of formula (I) in which R₃    represents the hydrogen atom,    which compound of formula (I) thus obtained can be reacted with a    compound of formula X₁NC(Y), X₂CO₂H or X₃SO₂Cl in which X₁, Y, X₂    and X₃ have the meaning indicated above, in order to obtain the    corresponding compound of formula I in which R₂ represents a radical    of formula —C(Y)NHX₁ and R₃ the —C(Y)—NHX₁, —C(O)X₂ or SO₂X₃ radical    respectively;-   B) or a compound of formula X₂CO₂H in which X₂ has the meaning    indicated above, in order to obtain a compound of formula (3)    which compound of formula (3) represents the corresponding compound    of formula (I) in which R₃ represents Me or Boc and which, when R₃    represents Boc, can be subjected to an acid treatment in order to    obtain the corresponding compound of formula (I) in which R₃    represents the hydrogen atom,    which compound of formula (I) thus obtained can be reacted with a    compound of formula X₁NC(Y), X₂CO₂H or X₃SO₂Cl in which X₁, Y, X₂    and X₃ have the meaning indicated above, in order to obtain the    corresponding compound of formula I in which R₂ represents a radical    of formula —C(O)X₂ and R₃ the —C(Y)—NHX₁, —C(O)X₂ or SO₂X₃ radical    respectively.

A more particular subject of the invention is also a preparationprocess, in solid phase, for compounds of formula I as defined above,characterized in that it comprisesthe reducing amination of the ketonic resin

in the presence of an amine of formula R₁NH₂ in which R₁ has the meaningindicated above, in order to obtain the compound of formula (4)

which compound of formula (4) is reacted with

-   A) either a compound of formula X₁NC(Y) in which X₁ and Y have the    meaning indicated above, in order to obtain a compound of formula    (5)    followed by cleavage of the resin in order to obtain the    corresponding compound of formula (I) in which R₃ represents the    hydrogen atom,-   B) or a compound of formula X₃SO₂Cl in which X₃ has the meaning    indicated above, in order to obtain a compound of formula (6)    followed by cleavage of the resin in order to obtain the    corresponding compound of formula (I) in which R₃ represents the    hydrogen atom,-   C) or a compound of formula X₂CO₂Cl in which X₂ has the meaning    indicated above, in order to obtain a compound of formula (7)    followed by cleavage of the resin in order to obtain the    corresponding compound of formula (I) in which R₃ represents the    hydrogen atom;-   D) or a compound of formula X₂CO₂H in which X₂ has the meaning    indicated above, in order to obtain a compound of formula (7) as    defined above, followed by cleavage of the resin in order to obtain    the corresponding compound of formula (I) in which R₃ represents the    hydrogen atom.

Finally a more particular subject of the invention is a preparationprocess, in solid phase, for compounds of formula I as defined above,characterized in that it comprisesthe reducing amination of the ketonic resin

in the presence of an amine of formula R₁NH₂ in which R₁ has the meaningindicated above, in order to obtain the compound of formula (8)

which compound of formula (8) is reacted with

-   A) either a compound of formula X₁NC(O) in which X₁ has the meaning    indicated above, in order to obtain a compound of formula (9)    which compound (9) thus formed is reacted with a compound of formula    R₃X in which R₃ is as defined above and X represents Br or I,    followed by cleavage of the resin in order to obtain the    corresponding compound of formula (I);-   B) or a compound of formula X₃SO₂Cl in which X₃ has the meaning    indicated above, in order to obtain a compound of formula (10)    which compound (10) thus formed is reacted with a compound of    formula R₃X in which R₃ is as defined above and X represents Br or    I, followed by cleavage of the resin in order to obtain the    corresponding compound of formula (I);-   C) or a compound of formula X₂CO₂Cl in which X₂ has the meaning    indicated above, in order to obtain a compound of formula (11)    which compound (11) thus formed is reacted with a compound of    formula R₃X in which R₃ is as defined above and X represents Br or    I, followed by cleavage of the resin in order to obtain the    corresponding compound of formula (I);-   D) or a compound of formula X₂CO₂H in which X₂ has the meaning    indicated above, in order to obtain a compound of formula (11) as    defined above,    which compound (11) thus formed is reacted with a compound of    formula R₃X in which R₃ is as defined above and X represents Br or    I, followed by cleavage of the resin in order to obtain the    corresponding compound of formula (I).

Compounds I of the present invention have useful pharmacologicalproperties. Thus it has been discovered that compounds I of the presentinvention have a high affinity for one (or more) of the somatostatinreceptors. They can be used as non-peptide agonists or antagonists ofsomatostatin in a selective or non-selective manner.

The compounds of the present invention can therefore be used indifferent therapeutic applications. They can advantageously be used totreat the pathological states or the diseases as presented above and inwhich one (or more) of the somatostatin receptors are involved.

An illustration of the pharmacological properties of the compounds ofthe invention will be found hereafter in the experimental part.

A subject of the present Application is also, as medicaments, theproducts of formula I as defined above, as well as the addition saltswith pharmaceutically acceptable mineral or organic acids of saidproducts of formula I, as well as the pharmaceutical compositionscontaining, as active ingredient, at least one of the medicaments asdefined above, in combination with a pharmaceutically acceptablesupport.

The pharmaceutical composition can be in the form of a solid, forexample, powders, granules, tablets, gelatin capsules or suppositories.Appropriate solid supports can be, for example, calcium phosphate,magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin,cellulose, methyl cellulose, sodium carboxymethyl cellulose,polyvinylpyrrolidine and wax.

The pharmaceutical compositions containing a compound of the inventioncan also be presented in liquid form, for example, solutions, emulsions,suspensions or syrups. Appropriate liquid supports can be, for example,water, organic solvents such as glycerol or glycols, similarly theirmixtures, in varying proportions, in water, with added pharmaceuticallyacceptable oils or fats. The sterile liquid compositions can be used forintramuscular, intraperitoneal or subcutaneous injections and thesterile compositions can also be administered intravenously.

Some compounds of the general formula I as defined above, are covered bythe patent application DE 2751138. This DE patent application describedcompounds which antagonise the effects of dopamine and endogenous orexogenous dopaminergic agents, and stimulate serotoninergic mechanism,activity which is far different from the activity of the compounds ofthe present invention.

A subject of the present invention is also the use of compounds ofgeneral formula I_(a)

in racemic, enantiomeric form or all combinations of these forms, inwhich:

-   R_(1a) represents a linear or branched (C₁-C₁₆)alkyl, alkenyl,    alkynyl, —(CH₂)_(m)—Y-Z₁₁ or —(CH₂)_(m)-Z₁₂ radical in which    -   Z₁₁ represents a (C₁-C₆)alkyl or aryl optionally substituted,    -   Z₁₂ represents cyano, cyclohexenyl, bis-phenyl,        (C₃-C₇)cycloalkyl, optionally substituted (C₃-C₇)        heterocycloalkyl, optionally substituted aryl or optionally        substituted heteroaryl,    -   or Z₁₂ represents a radical of formula        or R_(1a) represents a radical of formula-   R_(2a) represents a radical of formula —C(Y)NHX₁, —C(O)X₂ or SO₂X₃;-   R_(3a) represents the hydrogen atom, an optionally substituted    alkyl, alkenyl, alkynyl, optionally substituted aralkyl, optionally    substituted heteroarylalkyl radical, or a radical of formula    —C(Y)—NHX₁, —(CH₂)_(n)—C(O)X₂, SO₂X₃ or-   X₁ represents a linear or branched (C₁-C₁₅)alkyl, alkenyl, alkynyl,    —(CH₂)_(m)—Y-Z₂₁ or —(CH₂)_(p)Z₂₂ radical in which    -   Z₂₁ represents a (C₁-C₆)alkyl    -   Z₂₂ represents cyclohexenyl, indanyl, bis-phenyl,        (C₃-C₇)cycloalkyl, (C₃-C₇)heterocycloalkyl, mono- or        di-alkylamino, —C(O)—O-alkyl, or aryl or heteroaryl optionally        substituted,    -   or Z₂₂ represents a radical of formula-   X₂ represents a linear or branched (C₁-C₁₀)alkyl radical, an alkenyl    radical optionally substituted by a phenyl radical (the phenyl    radical being itself optionally substituted), an alkynyl radical, or    a radical of formula —(CH₂)_(m)-W-(CH₂)_(q)-Z₂₃ or —(CH₂)_(p)-U-Z₂₄    in which    -   Z₂₃ represents a (C₁-C₆)alkyl or aryl optionally substituted;    -   Z₂₄ represents alkyl, cyclohexenyl, bis-phenyl,        (C₃-C₇)cycloalkyl optionally substituted,        (C₃-C₇)heterocycloalkyl, cyano, amino, mono or di-alkylamino, or        aryl or heteroaryl optionally substituted,    -   or Z₂₄ represents a radical of formula        or X₂ represents a radical represented below:        where the protective group (PG) represents H or        tert-butyloxycarbonyl;-   X₃ represents a linear or branched (C₁-C₁₀)alkyl radical, an alkenyl    radical optionally substituted by a phenyl radical (the phenyl    radical being itself optionally substituted), CF₃, or —(CH₂)_(p)Z₂₅    in which    -   Z₂₅ represents aryl or heteroaryl optionally substituted,        or X₃ represents a radical of formula        optionally substituted by one or more halo radicals identical or        different;-   Y represents an oxygen or sulphur atom;-   W represents an oxygen or sulphur atom, or SO₂;-   U represents a covalent bond or the oxygen atom;-   n is an integer from 0 to 4;-   m is an integer from 1 to 6;-   p is an integer from 0 to 6;-   q is an integer from 0 to 2,    or their addition salts with pharmaceutically acceptable mineral or    organic acids, for the preparation of a medicament intended to treat    pathological states or diseases in which one (or more receptor(s) of    somatostatin is (are) involved.

A more particulary subject of the invention is the use of products ofgeneral formula I_(a) as defined above, characterized in that

-   i) the substituent or substituents which can be carried by the aryl    radicals represented by Z₁₁ and Z₁₂ and heteroaryl represented by    Z₁₂ are chosen independently from the fluoro, chloro, bromo, iodo,    alkyl, alkoxy, alkylthio, —CF₃, —OCF₃, phenyl, phenoxy,    aminosulphonyl radicals;-   ii) the substituent or substituents which can be carried by the    heterocycloalkyl radical represented by Z₁₂ are chosen independently    from the oxy and alkyl radicals;-   iii) the substituent or substituents which can be carried by the    aryl and heteroaryl radicals represented by Z₂₂ are chosen    independently from the fluoro, chloro, bromo, iodo, alkyl, alkenyl,    alkoxy, alkylthio, CF₃, OCF₃, nitro, cyano, azido, aminosulphonyl,    piperidinosulphonyl, mono- or di-alkylamino, —C(O)—O-alkyl,    —C(O)-alkyl, or phenyl, phenoxy, phenylthio, benzyloxy radicals, the    phenyl radical being able to be substituted;-   iv) the substituent or substituents which can be carried by the aryl    radicals represented by Z₂₃ and Z₂₄, cycloalkyl and heteroaryl    represented by Z₂₄ are chosen independently from the fluoro, chloro,    bromo, iodo, alkyl, alkoxy, alkylthio, CF₃, OCF₃, OCHF₂, SCF₃,    nitro, cyano, azido, hydroxy, —C(O)O-alkyl, —O—C(O)-alkyl,    —NH—C(O)-alkyl, alkylsulphonyl, mono- or di-alkylamino, amino,    aminoalkyl, pyrrolyl, pyrrolydinyl or the radicals phenyl, phenoxy,    phenylthio, benzyl, benzyloxy radicals the aryl radical of which is    optionally substituted by one or more alkyl, CF₃ or halo radicals;-   v) the substituent or substituents which can be carried by the aryl    and heteroaryl radicals represented by Z₂₅ are chosen independently    from the fluoro, chloro, bromo, iodo, alkyl, alkoxy, CF₃, OCF₃,    nitro, cyano, —NH—C(O)-alkyl, alkylsulphonyl, amino, mono- and    di-alkylamino, phenyl, pyridino radicals;-   vi) the substituent which can be carried by the alkyl radical    represented by R₃ is the cyano radical.-   vii) the substituent or substituents which can be carried by the    aralkyl radical represented by R₃ are chosen independently from the    fluoro, chloro, bromo, iodo, alkyl, alkoxy, CF₃, OCF₃, OCHF₂, SCF₃,    SCHF₂, nitro, cyano, —C(O)O-alkyl, alkylsulphonyl, thiadiazolyl    radicals, or the phenyl and phenoxy radicals the phenyl radical of    which is optionally substituted by one or more halo radicals.-   viii) the substituent or substituents which can be carried by the    heteroarylalkyl radical represented by R₃ are chosen independently    from the fluoro, chloro, bromo or nitro radicals.

A more particular subject of the present invention is the use ofcompounds of general formula I_(a) as defined above in which R_(1a)represents a linear or branched (C₁-C₆)alkyl radical, the—(CH₂)_(m)—Y-Z₁₁ or —(CH₂)_(m)-Z₁₂ radical in which

-   -   Z₁₁ represents a (C₁-C₆)alkyl,    -   Z₁₂ represents bis-phenyl, (C₃-C₇)cycloalkyl,        (C₃-C₇)heterocycloalkyl optionally substituted, or aryl or        heteroaryl optionally substituted by one or more substituents        chosen independently from the fluoro, chloro, bromo, iodo,        alkyl, alkoxy radicals,    -   or Z₁₂ represents    -   Y represents the oxygen atom,        or R_(1a) represents a radical of formula

A more particular subject of the present invention is the use ofcompounds of general formula I_(a) as defined above in which R_(2a)represents a radical of formula —C(Y)NHX₁, —C(O)X₂ or SO₂X₃ in which

-   -   X₁ represents a linear or branched (C₁-C₁₅)alkyl radical, or        —(CH₂)_(p)Z₂₂ in which        -   Z₂₂ represents cyclohexenyl, bis-phenyl, (C₃-C₇)cycloalkyl,            (C₃-C₇)heterocycloalkyl, mono- or di-alkylamino,            —C(O)—O-alkyl, or aryl or heteroaryl optionally substituted            by one or more radicals chosen independently from the            fluoro, chloro, bromo, iodo, alkyl, alkoxy, alkylthio, CF₃,            OCF₃, nitro, cyano, azido, piperidinosulphonyl,            —C(O)—O-alkyl, —C(O)-alkyl, or phenyl radicals,        -   or Z₂₂ represents a radical of formula    -   X₂ represents a linear or branched (C₁-C₁₀)alkyl, alkynyl,        —(CH₂)_(m)-W-(CH₂)_(q)-Z₂₃ or —(CH₂)_(p)-U-Z₂₄ radical in which        -   W represents SO₂,        -   U represents a covalent bond,        -   Z₂₃ represents an aryl radical        -   Z₂₄ represents cyclohexenyl, bis-phenyl, (C₃-C₇)cycloalkyl            optionally substituted by an aminoalkyl, or aryl or            heteroaryl radical optionally substituted by one or more            radicals chosen from fluoro, chloro, bromo, iodo, alkyl,            alkoxy, —CF₃, —OCF₃, SCF₃, hydroxy, —O—C(O)-alkyl, mono- or            di-alkylamino, amino        -   or Z₂₄ represents a radical of formula    -   or X₂ represents    -   X₃ represents a —(CH₂)_(p)Z₂₅ radical in which Z₂₅ represents an        aryl radical optionally Substituted by one or more identical or        different radicals chosen from alkoxy and CF₃.

A more particular subject of the present invention is the use ofcompounds of general formula I_(a) as defined above in which R_(3a)represents the hydrogen atom, an alkyl, alkenyl, heteroarylalkyl radicaloptionally substituted or a radical of formula —C(Y)—NHX₁, —C(O)X₂ orSO₂X₃ in which

-   -   X₁ represents a —(CH₂)_(p)Z₂₂ radical in which        -   Z₂₂ represents an aryl radical optionally substituted by one            or more radicals chosen independently from the fluoro,            chloro, bromo, iodo, alkyl, alkoxy, CF₃, nitro, phenoxy            radicals;    -   X₂ represents the vinyl radical substituted by a phenyl, the        phenyl radical being itself optionally substituted by one or        more halo, or —(CH₂)_(p)-U-Z₂₄ radicals in which        -   Z₂₄ represents alkyl, (C₃-C₇)cycloalkyl,            (C₃-C₇)heterocycloalkyl, bis-phenyl, amino, mono or            di-alkylamino, or aryl or heteroaryl optionally substituted            by one or more radicals chosen from alkoxy, bromo, chloro,            fluoro, hydroxy, CF₃, nitro, amino, mono- and di-alkylamino,            pyrrolyl,            or X₂ represents a radical of formula    -   X₃ represents a linear or branched (C₁-C₁₀)alkyl radical, the        vinyl radical substituted by a radical (the phenyl radical being        itself optionally substituted), CF₃, or —(CH₂)_(p)Z₂₅ in which        -   Z₂₅ represents aryl or heteroaryl optionally substituted by            one or more substituents chosen independently from the            fluoro, chloro, bromo, iodo, alkyl, alkoxy, CF₃, nitro,            —NH—C(O)-alkyl, mono- and di-alkylamino radicals.

Preferentially, R_(1a) represents a linear or branched (C₁-C₆)alkylradical, the —(CH₂)_(m)—Y-Z₁₁ or —(CH₂)_(m)-Z₁₂ radical in which

-   -   Z₁₁ represents a (C₁-C₆)alkyl,    -   Z₁₂ represents naphthyl, morpholino, bis-phenyl, pyrrolidinyl        substituted by the oxy radical, or the phenyl, piperazinyl,        pyridinyl and indolyl radicals which are optionally substituted        by one or more substituents chosen independently from the bromo,        fluoro, chloro, alkyl, alkoxy, —CF₃, —OCF₃ radicals    -   or Z₁₂ represents    -   Y represents the oxygen atom,        or R_(1a) represents a radical of formula given below:

Preferentially, R_(2a) represents a radical of formula —C(Y)NHX₁,—C(O)X₂ or SO₂X₃ in which

-   -   X₁ represents a linear or branched (C₁-C₁₀)alkyl, or        —(CH₂)_(p)Z₂₂ radical in which        -   Z₂₂ represents cyclohexyl, cyclohexenyl, bis-phenyl,            morpholino, piperidino, mono- or di-alkylamino,            —C(O)—O-alkyl, or phenyl, naphthyl or furyl optionally            substituted by one or more radicals chosen independently            from the fluoro, chloro, bromo, iodo, alkyl, alkoxy,            alkylthio, CF₃, OCF₃, nitro, cyano, azido,            piperidinosulphonyl, —C(O)—O-alkyl, —C(O)-alkyl or phenyl            radicals,        -   or Z₂₂ represents a radical of formula    -   X₂ represents an alkyl, alkynyl, —(CH₂)_(m)-W-(CH₂)_(q)-Z₂₃ or        —(CH₂)_(p)Z₂₄ radical in which        -   W represents SO₂;        -   Z₂₃ represents the phenyl radical;        -   Z₂₄ represents cyclohexenyl, bis-phenyl, cyclohexyl            optionally substituted by an aminoalkyl, or phenyl,            naphthyl, benzothienyl, thienyl or indolyl radical            optionally substituted by one or more radicals chosen from            fluoro, chloro, bromo, iodo, alkyl, alkoxy, —CF₃, —OCF₃,            SCF₃, hydroxy, —O—C(O)-alkyl, —NH—C(O)-alkyl, mono- or            di-alkylamino, amino, or        -   Z₂₄ represents a radical of formula    -   or X₂ represents    -   X₃ represents a —(CH₂)_(p)Z₂₅ radical in which Z₂₅ represents        the phenyl radical optionally substituted by one or more        identical or different radicals chosen from alkoxy and CF₃,

Preferentially, R_(3a) represents the hydrogen atom, an alkyl, alkenylor furyl-methyl radical substituted by one or more nitro radicals, or aradical of formula —C(Y)—NHX₁, —C(O)X₂ or SO₂X₃ in which

-   -   X₁ represents a —(CH₂)_(p)Z₂₂ radical in which        -   Z₂₂ represents the phenyl or naphthyl radical optionally            substituted by one or more radicals chosen independently            from the fluoro, chloro, bromo, iodo, alkyl, alkoxy, CF₃,            nitro, phenoxy radicals,    -   X₂ represents the vinyl radical substituted by a phenyl radical        itself optionally substituted by one or more halo, or        —(CH₂)_(p)-U-Z₂₄ radicals in which        -   Z₂₄ represents alkyl, cyclohexyl, tetrahydrofuryl,            bis-phenyl, amino, mono or di-alkylamino, or phenyl,            indolyl, thienyl, pyridinyl, benzothienyl and furyl            optionally substituted by one or more radicals chosen from            alkoxy, bromo, chloro, fluoro, amino, mono- and            di-alkylamino, nitro, hydroxy, pyrrolyl    -   or X₂ represents a radical of formula    -   X₃ represents a linear or branched (C₁-C₁₀)alkyl radical, the        vinyl radical substituted by a phenyl, CF₃, or —(CH₂)_(p)Z₂₅        radical in which        -   Z₂₅ represents a phenyl, naphtyl, thienyl, pyrazolyl or            thiazolyl radical optionally substituted by one or more            substituents chosen independently from the fluoro, chloro,            bromo, iodo, alkyl, alkoxy, CF₃, nitro, —NH—C(O)-alkyl,            mono- and di-alkylamino radicals;

Very preferentially, R_(1a) represents the —(CH₂)_(m)Z₁₂ radical inwhich m=2 and Z₁₂ represents bis-phenyl or the radical indolylsubstituted by one or more substituents chosen independently from thealkyl and alkoxy radicals.

Very preferentially, R_(2a) represents the radicals of formula —C(Y)NHX₁and —C(O)X₂ in which

-   -   Y represents S;    -   X₁ represents a phenyl radical optionally substituted by one or        more azido radicals,    -   X₂ represents —(CH₂)_(p)Z₂₄ in which        -   p is equal to 1, 2 or 3,        -   Z₂₄ represents cyclohexyl, or phenyl or benzothienyl            optionally substituted by one or more radicals chosen from            fluoro, chloro, bromo, iodo or —CF₃.

Very preferentially, R_(3a) represents the hydrogen atom or the methylradical.

All the technical and scientific terms used in the present text have themeaning known to a person skilled in the art. Furthermore, all patents(or patent applications) as well as other bibligraphical references areincorporated by way of reference.

Experimental Part:

Other compounds according to the invention obtained according to theprocedures of Examples A, B, C and D described previously, are set outin the table below.

The compounds are characterized by their retention time (rt), expressedin minutes, and their molecular peak (M+H+) determined by massspectroscopy (MS).

For the mass spectroscopy, a single quadripole mass spectrometer(Micromass, Platform model) equipped with an electrospray source is usedwith a resolution of 0.8 Da at 50% valley. The conditions for Examples 1to 778 below, are as follows:

Conditions C1 and C2

-   Eluent: A: Water+0.02% trifluoracetic acid; B: acetonitrile

T (min) A % B % 0 100 0 1 100 0 10 15 85 12 15 85

Condition C1 Condition C2 Flow rate: 1.1 ml/min Flow rate: 1.1 ml/minInjection: 5 μl Injection: 20 μl Temp: 40° C. Temp :40° C. Wavelength (%UV): 210 nm Wavelength (% UV): 210 nm Column: Uptisphere ODS 3 μmColumn: Kromasyl ODS 3.5 μm 33 * 46 mm i.d 50 * 4.6 mm i.dConditions C3

-   Eluent: A: Water+0.02% trifluoracetic acid; B: acetonitrile

T (min) A % B % 0 90 10 6 15 85 10 15 85

-   Flow rate: 1 ml/min-   Injection: 5 μl-   Column: Uptisphere ODS 3 μm 50*4.6 mm i.d-   Temp: 40° C.-   Wavelength (% UV): 220 nm

The conditions depending on the examples, are as follows:

Examples Conditions  1 to 29  C2  30 to 263 C1 264 to 425 C3 426 to 456C2 457 to 503 C3 504 to 586 C1 587 to 778 C3

These examples are presented to illustrate the above procedures andshould in no considered as limiting the scope of the invention.

Ex R₁ R₂ R₃ Purity (%) rt M + H + 1

66 7.6 523.3 2

94 7.7 543.2 3

96 8.1 557.2 4

98 8.5 593.2 5

95 7.8 557.2 6

97 8.1 623.1 7

95 8.1 588.2 8

19 8.1 535.2 9

99 8.5 622.2 10

80 8.4 611.2 11

99 8.2 569.2 12

93 8.9 656.2 13

85 9.1 697.0 14

95 8.7 611.2 15

87 7.8 573.2 16

100 8.4 653.2 17

97 8.6 611.1 18

99 8.7 636.3 19

83 7.2 621.2 20

98 7.4 595.2 21

84 7.4 536.3 22

99 8.4 614.3 23

63 8.2 570.2 24

92 7.5 572.3 25

93 8.4 606.4 26

96 7.4 582.3 27

93 8.1 624.2 28

93 7.8 602.2 29

95 7.4 585.2 30

87.39 4.0 516.4 31

92 5.5 560.3 32

90 5.7 563.3 33

87.73 5.6 625.4 34

85.41 6.0 565.4 35

98.4 6.4 671.1 36

86 4.9 542.3 37

89 6.1 572.3 38

77.61 6.8 555.4 39

89.16 4.2 545.4 40

93.32 5.3 599.3 41

83 6.0 589.2 42

36.3 5.9 531.2 43

83.27 5.9 555.3 44

82 4.5 564.4 45

86.75 6.0 577.3 46

91.95 4.7 501.4 47

88.94 4.5 475.3 48

73 5.3 542.3 49

90.96 4.4 486.4 50

95.5 5.9 530.4 51

94.51 6.1 533.4 52

93.64 6.0 595.4 53

96.05 6.5 535.4 54

84.68 6.9 641.1 55

86 5.5 512.3 56

92 6.5 542.4 57

91.29 7.2 525.5 58

94.7 4.7 515.4 59

94 5.8 569.3 60

89.43 6.6 559.3 61

32 6.9 501.5 62

93.53 6.4 525.4 63

94.7 4.9 534.4 64

94.32 6.4 547.3 65

91.71 5.2 471.4 66

92.47 5.0 445.4 67

58 5.9 512.3 68

84.55 3.6 559.4 69

87.7 4.7 603.4 70

90.77 4.8 606.4 71

72.34 4.8 668.4 72

87.18 5.1 608.4 73

69.52 5.4 714.1 74

63.39 4.2 585.3 75

54.46 5.1 615.4 76

87.3 5.7 598.4 77

96.1 3.8 588.4 78

89.9 4.5 642.3 79

61.5 5.1 632.3 80

43.65 5.0 574.3 81

88.18 5.0 598.3 82

88.6 4.0 607.4 83

90.08 5.1 620.3 84

85.57 4.0 544.3 85

48.41 4.5 585.3 86

82.68 6.1 589.3 87

79.99 6.5 611.4 88

86.07 4.8 503.4 89

82 5.1 551.4 90

19.44 4.4 502.4 91

86.48 5.1 550.4 92

80 6.3 567.3 93

94.62 6.6 559.3 94

57.01 6.9 581.4 95

92 5.2 473.4 96

87.4 5.6 521.4 97

20.99 5.0 472.4 98

88.63 5.7 520.4 99

84 6.7 537.3 100

89.71 5.2 632.2 101

90.25 5.5 654.4 102

90.09 4.0 546.4 103

71 4.4 594.3 104

37.19 3.8 545.3 105

76.55 4.5 593.4 106

69.62 5.9 405.2 107

98 7.1 493.2 108

80 6.0 467.3 109

88 6.5 471.2 110

60.04 5.7 427.3 111

78 6.5 515.2 112

97 6.2 455.2 113

70 5.7 489.3 114

90 6.2 493.3 115

62.88 3.6 305.3 116

82.99 4.7 393.2 117

74.42 5.0 393.1 118

10.53 5.4 367.3 119

74.79 4.3 371.2 120

50.14 3.4 327.3 121

70 4.3 415.2 122

84 3.9 355.3 123

66 3.5 389.3 124

94.61 3.9 393.2 125

71 5.5 462.3 126

52 6.6 550.2 127

57 6.8 550.1 128

60 5.6 524.2 129

64 6.1 528.2

Ex R₁ R₂ R₃ Purity (%) rt M + H + 130

27 5.4 484.3 131

51 6.2 572.2 132

73 5.7 512.2 133

61 5.4 546.2 134

43 5.8 550.2 135

76 5.3 483.3 136

49 6.4 571.2 137

63 6.6 571.1 138

79 5.4 545.2 139

57 5.9 549.2 140

66.58 5.2 505.3 141

61 6.0 593.2 142

67 5.5 533.2 143

61 5.2 567.3 144

51 5.6 571.2 145

56 7.0 457.3 146

64 8.1 545.2 147

52 8.3 545.2 148

69 7.1 519.3 149

70 7.6 523.3 150

63.77 6.7 479.4 151

50 7.3 567.3 152

46 7.3 507.3 153

78 6.7 541.3 154

66 7.0 545.3 155

68 6.0 457.2 156

65 7.1 545.2 157

67 7.3 545.1 158

66 6.1 519.2 159

77 6.6 523.2 160

60.49 5.8 479.3 161

60 6.6 567.3 162

69 6.2 507.2 163

50 5.8 541.2 164

49 6.2 545.2 165

67 4.4 466.3 166

45 5.5 554.2 167

65.89 5.7 554.1 168

5 5.4 528.2 169

64.08 5.0 532.2 170

62.51 4.3 488.3 171

55 5.2 576.3 172

50.35 4.7 516.3 173

7 5.2 550.3 174

48.63 4.8 554.3 175

53 5.7 459.2 176

49 6.9 547.2 177

61 7.1 547.1 178

57 5.9 521.2 179

65 6.4 525.2 180

88.99 5.6 481.3 181

58 6.4 569.2 182

64 6.0 509.2 183

63 6.0 547.2 184

67.83 10.1 516.3 185

61.66 6.7 525.3 186

40.48 9.9 537.3 187

50 6.4 546.3 188

42.57 7.4 478.4 189

29 4.8 487.3 190

55 10.3 499.3 191

19.39 6.7 508.3 192

67 11.1 567.3 193

64.73 7.9 576.3 194

92 10.6 586.3 195

85 7.3 595.3 196

96 10.5 607.3 197

89.25 7.2 616.3 198

98.24 7.9 548.3 199

94 5.6 557.3 200

98 10.8 569.2 201

93.17 7.3 578.2 202

97.82 11.7 637.3 203

88.11 8.5 646.3 204

73 11.2 690.0 205

60.44 7.9 699.0 206

76 11.1 711.0 207

72.2 7.8 720.0 208

89.42 8.5 652 209

48 6.2 659.0 210

78.2 11.6 673.0 211

66.1 7.9 682.0 212

78 12.6 739.1 213

88.77 9.1 750.0 214

73 10.6 604.3 215

67 7.5 613.2 216

73 10.5 625.3 217

83 7.3 634.2 218

87.32 7.9 566.3 219

79 5.7 575.2 220

89 10.7 587.2 221

78.75 7.4 596.2 222

95 11.6 655.3 223

79 8.6 664.3 224

58 9.4 614.2 225

78 6.4 623.2 226

75 9.2 635.3 227

88 6.1 644.3 228

86 6.7 576.3 229

80 4.6 585.2 230

73 9.5 597.2 231

66 6.2 606.2 232

62 10.5 665.3 233

81 7.5 674.3 234

92 8.9 540.3 235

86 5.6 549.2 236

91 8.7 561.3 237

94.51 5.4 570.2 238

93.36 6.2 502.3 239

97 3.8 511.3 240

98.13 9.0 523.3 241

82 5.4 532.2 242

99 10.1 591.3 243

94.74 6.8 600.3 244

89 9.8 596.3 245

81 6.6 605.3 246

96 9.7 617.3 247

85.68 6.4 626.3 248

98.65 7.1 558.3 249

92 4.8 567.2 250

96 10.0 579.2 251

88.12 6.5 588.2

Ex R₁ R₂ R₃ Purity (%) rt M + H + 252

97 10.9 647.3 253

86 7.8 656.3 254

79 10.1 572.2 255

79 7.0 581.2 256

71 10.0 593.3 257

72.74 6.6 602.2 258

79.1 7.4 534.3 259

74 4.9 543.2 260

84.17 10.3 555.2 261

76.16 6.7 564.2 262

95 11.1 623.3 263

78.91 8.0 632.3 264

75.26 5.1 430.2 265

90.43 5.0 430.3 266

74.93 4.3 452.3 267

79.62 4.9 390.3 268

92.82 5.6 490.4 269

68.87 3.6 421.3 270

79.07 4.9 440.2 271

84.22 3.0 392.3 272

67.34 4.9 418.2 273

81.63 4.4 352.3 274

90.11 4.7 342.3 275

54.36 4.3 438.3 276

81.69 4.9 432.2 277

85.62 5.2 382.3 278

86.19 3.2 377.3 279

94.76 4.9 451.2 280

99.42 4.7 451.3 281

90.55 4.0 473.3 282

93.80 4.6 411.3 283

82.71 5.4 511.4 284

90.85 3.4 442.3 285

98.65 4.6 461.2 286

98.80 2.8 404.3 287

86.02 4.6 439.3 288

97.47 4.1 373.3 289

99.31 4.4 363.3 290

45.77 4.1 459.3 291

94.07 4.6 453.3 292

95.65 5.0 403.4 293

94.30 2.9 398.3 294

80.64 5.9 481.2 295

98.05 5.7 481.3 296

94.93 5.0 503.4 297

96.81 5.6 441.3 298

95.00 6.3 541.4 299

95.13 4.2 472.4 300

52.68 3.2 452.4 301

98.03 5.6 491.2 302

96.44 3.7 217.9 303

97.22 5.6 469.3 304

96.97 5.2 403.3 305

99.05 5.4 393.4 306

32.67 5.1 489.3 307

84.51 5.6 483.3 308

98.44 6.0 433.4 309

97.78 4.0 428.3 310

79.54 5.0 460.2 311

78.59 4.9 460.3 312

66.24 4.2 482.3 313

70.15 4.8 420.3 314

57.87 5.5 520.4 315

71.26 3.6 451.3 316

81.16 4.8 470.2 317

74.96 2.9 413.3 318

53.47 4.8 448.3 319

87.88 4.3 382.3 320

91.41 4.6 372.3 321

1.59 5.0 468.3 322

77.81 4.8 462.3 323

76.59 5.1 412.3 324

83.35 3.1 407.3 325

87.42 5.2 444.2 326

98.89 5.1 444.3 327

95.68 4.3 466.3 328

97.27 4.9 404.3 329

95.73 5.7 504.4 330

83.37 3.7 435.3 331

71.88 3.2 413.3 332

98.33 5.0 454.2 333

83.73 3.0 397.3 334

94.77 5.0 432.3 335

95.88 4.5 366.3 336

98.9 4.7 356.3 337

50.74 4.4 452.3 338

95.39 5.0 446.3 339

98.2 5.3 396.3 340

92.35 3.2 391.3 341

90.41 5.1 444.2 342

87.41 5.0 444.3 343

87.37 4.3 466.3 344

83.01 4.9 404.3 345

89.47 5.6 504.4 346

77.55 3.6 435.3 347

49.49 2.4 414.3 348

85.63 4.9 454.2 349

88.12 2.9 397.3 350

87.73 4.9 432.3 351

84.48 4.4 366.3 352

82.03 4.7 356.3 353

82.93 4.9 446.3 354

72.6 5.3 396.3 355

86.75 3.2 391.3 356

93.75 4.7 413.1 357

96.13 4.6 413.2 358

98.3 3.8 435.2 359

96.45 4.5 373.2 360

97.9 5.3 473.4 361

97.57 3.0 404.3 362

78.0 2.5 383.2 363

98.96 4.5 423.1 364

93.98 2.4 366.3 365

97.98 4.5 401.2 366

93.33 4.0 335.2 367

95.73 4.3 325.3 368

1.21 3.9 421.3

Ex R₁ R₂ R₃ Purity (%) rt M + H + 369

88.55 4.6 415.2 370

95.93 4.9 365.3 371

99.1 2.6 360.2 372

90.59 3.4 392.1 373

93.57 3.3 392.2 374

97.23 2.6 414.2 375

93.83 3.1 352.3 376

96.81 4.0 452.4 377

97.7 2.2 383.3 378

53.69 2.3 362.2 379

97.2 3.1 402.1 380

70.3 2.5 345.3 381

97.59 3.1 380.2 382

86.74 2.4 314.2 383

87.28 2.6 304.3 384

10.27 3.1 400.2 385

93.38 3.1 394.2 386

88.99 3.4 344.3 387

89.43 2.5 339.3 388

86.18 4.2 458.3 389

37.01 3.9 404.3 390

57.02 2.7 437.4 391

78.70 4.3 441.3 392

67.94 4.6 490.3 393

39.75 4.5 479.3 394

94.48 2.8 435.4 395

83.7 3.4 432.3 396

96.5 4.7 464.4 397

43.75 4.5 547.3 398

86.87 3.3 399.3 399

47.77 2.9 345.3 400

82 3.4 382.3 401

97.10 3.8 431.2 402

76.92 3.8 420.2 403

97.3 2.8 373.3 404

95.9 4.0 405.3 405

69.50 3.7 488.3 406

90.79 4.1 420.3 407

86.38 2.5 399.3 408

67.52 4.6 452.2 409

99.8 2.7 397.3 410

97.7 3.3 394.3 411

87.97 5.0 488.3 412

97.23 3.6 467.4 413

99.29 3.7 465.4 414

96.2 4.2 462.4 415

72.0 5.5 494.3 416

85.09 4.3 467.3 417

68.52 4.1 413.3 418

98.76 2.8 446.4 419

73.21 4.4 450.3 420

76.94 4.7 499.2 421

85.12 4.6 488.2 422

98.15 2.9 444.4 423

58 5.1 477.3 424

25 3.6 410.3 425

69.90 4.6 556.3 426

90.11 8.2 556.3 427

95.30 9.7 552.3 428

89.35 9.6 573.3 429

97.48 11.8 547.4 430

91.35 9.6 591.3 431

66.60 9.7 557.3 432

97.25 10.5 547.3 433

98.20 10.2 549.3 434

88.28 4.7 489.3 435

94.30 5.8 485.3 436

92.92 5.6 506.3 437

95.73 7.1 480.4 438

89.80 5.6 524.3 439

69.38 5.6 490.3 440

95.21 6.2 480.3 441

96.98 6.0 482.3 442

85.00 5.4 456.3 443

94.40 6.5 452.3 444

91.10 6.3 473.3 445

96.60 7.7 447.3 446

92.80 6.3 491.2 447

85.40 6.3 457.2 448

96.70 6.9 447.2 449

98 6.7 449.2 450

38.17 3.6 385.2 451

92.70 3.4 406.2 452

89.50 4.7 380.3 453

86.24 3.4 424.2 454

71.20 3.3 390.2 455

88.60 3.8 380.2 456

89.26 3.5 382.2 457

96.55 4.9 445.3 458

94.46 4.8 455.2 459

95.6 4.7 411.3 460

98.1 5.0 461.3 461

93.31 5.1 419.4 462

97.08 4.2 402.3 463

94.61 4.4 395.3 464

97.05 4.9 503.2 465

95.13 5.1 453.4 466

93.21 4.8 475.3 467

94.08 4.7 485.2 468

93.08 4.6 441.3 469

95.17 4.9 491.3 470

89.99 5.0 449.4 471

92 4.1 432.3 472

94.71 4.3 425.3 473

95.3 4.8 533.2 474

94.13 5.0 483.4 475

95 5.1 459.3 476

94.69 5.0 469.2 477

94.44 4.9 425.3 478

98 5.2 475.3 479

96.2 5.3 433.4 480

93 4.4 416.3 481

94.59 4.6 409.3 482

95.22 5.1 517.2 483

95.7 5.3 467.4 484

94.8 4.6 457.2 485

86.7 4.5 420.3 486

88.5 4.8 447.3 487

96.9 5.1 483.4 488

92.3 4.7 505.2 489

65.4 4.9 471.2 490

62.6 4.7 434.3 491

57.9 5.0 461.3 492

94.2 5.3 497.4 493

54.0 5.0 519.2 494

54.6 4.8 501.3

Ex R₁ R₂ R₃ Purity (%) rt M + H + 495

64.9 4.7 464.3 496

70.4 4.9 491.3 497

96.5 5.2 527.4 498

55.7 4.9 549.2 499

57.4 5.1 485.3 500

59.3 4.9 448.4 501

53.6 5.2 475.3 502

97.8 5.4 511.4 503

10 + 36.87 5.2 533.2 504

96.33 11.2 646.3 505

92.67 9.4 690.1 506

41.11 9.5 656.2 507

97.65 10.1 646.2 508

96.29 9.9 648.2 509

90.89 8.5 501.3 510

61.04 5.8 401.2 511

99.16 10.5 496.4 512

95.73 7.1 396.3 513

66 9.3 496.3 514

95.00 8.9 396.2 515

96.61 9.5 530.3 516

94.05 6.4 430.3 517

87 8.6 536.3 518

91.59 5.6 436.3 519

86.84 8.4 522.3 520

94.18 5.4 422.3 521

99.75 10.4 517.4 522

96.8 6.8 417.4 523

70.34 9.1 517.3 524

93.49 5.8 417.3 525

93.03 9.3 551.3 526

97.13 6.1 451.3 527

74.37 8.4 557.3 528

92.92 5.3 457.3 529

92.92 8.8 484.3 530

92.68 5.5 384.2 531

98.29 10.8 479.3 532

96.39 7.0 379.3 533

99 9.5 479.2 534

99.76 6.0 379.2 535

99.17 9.7 513.2 536

99.74 6.3 413.2 537

68.71 8.7 519.3 538

90.09 5.4 419.3 539

91.37 9.8 552.3 540

95.39 6.6 452.3 541

98.71 11.7 547.4 542

99.02 7.9 447.4 543

79.38 10.5 547.3 544

95.46 7.1 447.3 545

95.3 10.6 581.3 546

95.45 7.3 481.3 547

80.92 9.8 587.3 548

92.06 6.5 487.3 549

63 7.7 529.4 550

79 7.1 495.4 551

70 6.7 529.3 552

77 6.3 495.3 553

61 6.9 563.3 554

69 6.5 529.3 555

69 6.1 569.3 556

76 5.8 535.3 557

79 5.9 555.3 558

88 5.6 521.3 559

90.81 7.4 550.4 560

95.6 6.9 516.4 561

80.85 6.4 550.3 562

85.8 6.0 516.3 563

92.92 6.6 584.3 564

97.26 6.3 550.3 565

82.91 5.8 590.3 566

87.77 5.5 556.3 567

86 6.0 517.3 568

83.41 5.7 483.3 569

95 7.6 512.3 570

94.08 7.1 478.4 571

87.39 6.5 512.3 572

90.06 6.1 478.3 573

85.61 6.8 546.2 574

83.51 6.4 512.3 575

78.63 5.9 552.3 576

79.58 5.6 518.3 577

84 7.1 585.3 578

91 6.7 551.3 579

89.59 8.6 580.4 580

97.13 7.9 546.4 581

83 7.6 580.3 582

92.05 7.1 546.3 583

86 7.8 614.3 584

95.49 7.3 580.3 585

77 7.0 620.3 586

91.1 6.6 586.4 587

95 4.6 435 588

90 4.4 391.3 589

88 5.1 435.3 590

92 4.9 447.3 591

20.32 5.1 399.4 592

85 5.3 486.3 593

97 5.1 442.3 594

92 5.7 486.4 595

79 5.5 498.3 596

93.4 4.68 451.29 597

94.9 4.86 425.27 598

97.9 5.37 475.22 599

97.1 5.20 457.32 600

95.1 5.10 441.24 601

91.1 4.61 481.29 602

97.5 4.78 455.29 603

98.0 5.28 505.22 604

95.4 5.12 487.33 605

94.0 5.03 471.27 606

89.8 4.86 465.29 607

98.2 5.03 439.29 608

97.6 5.53 489.24 609

93.3 5.36 471.34 610

91.4 5.27 455.26 611

94 4.9 459.3 612

92.95 4.8 469.2 613

91.61 4.7 425.3 614

92 5.0 475.3 615

85.2 5.1 433.4 616

83 4.2 416.3 617

94.11 4.4 409.3 618

93.85 5.0 517.2 619

92.74 5.1 467.4 620

91 4.8 489.3 621

91.9 4.7 499.3 622

89.71 4.6 455.3 623

90 4.9 505.3 624

83.96 5.0 463.4 625

87 4.1 446.3 626

93.1 4.3 439.3 627

93.21 4.8 547.2

Ex R₁ R₂ R₃ Purity (%) rt M + H + 628

90.67 5.0 497.4 629

79.6 4.9 485.2 630

72.8 4.8 448.3 631

78.7 5.1 475.3 632

97.3 5.4 511.4 633

51.5 5.1 533.2 634

76.1 4.9 515.3 635

74.2 4.7 478.3 636

76.5 5.0 505.3 637

97.7 5.3 541.4 638

71.4 5.0 563.2 639

82.54 4.4 451.3 640

93.42 4.2 397.3 641

98.93 2.9 430.4 642

81.46 4.5 434.3 643

96.41 4.9 483.3 644

91.55 4.7 472.3 645

97.96 2.9 428.4 646

96.9 5.0 425.3 647

95.8 4.9 457.3 648

91.41 4.6 540.3 649

88.0 4.75 465.3 650

99.0 4.89 439.3 651

98.5 5.42 489.2 652

93.3 5.24 471.3 653

87.6 5.14 455.3 654

88.3 4.66 495.3 655

98.1 4.82 469.3 656

98.4 5.34 519.2 657

95.4 5.16 501.3 658

89.8 5.08 485.3 659

80.76 4.84 410.2 660

61.69 4.97 426.2 661

90.93 4.79 454.1 662

91.55 4.58 394.2 663

91.99 4.88 454.1 664

92.79 5.55 526.2 665

93.78 5.02 502.1 666

96.3 4.75 408.2 667

81.2 5.02 408.2 668

90.79 4.74 440.2 669

78.93 4.88 456.3 670

91.87 4.69 484.2 671

91.19 4.51 424.2 672

95.27 4.79 484.2 673

89.5 5.46 542.2 674

90.77 4.92 532.1 675

95.1 4.66 438.2 676

88.7 4.92 524.2 677

81.65 4.99 424.2 678

70.32 5.11 440.3 679

90.06 4.96 468.2 680

94.11 4.74 408.2 681

93.96 5.04 468.2 682

93.3 5.66 540.2 683

94.79 5.16 516.1 684

96.5 4.9 422.3 685

88.2 5.19 438.2 686

87.93 4.86 424.2 687

84.74 5 440.2 688

95.34 4.82 468.2 689

89.78 4.6 408.2 690

95.16 4.9 468.1633 691

95.6 5.56 540.2 692

95.24 5.05 516.3 693

96.6 4.8 422.2 694

90.4 5.04 438.2 695

93.12 4.78 454.2 696

86.11 4.92 470.3 697

94.89 4.73 498.2 698

94.1 4.54 438.3 699

95.66 4.81 498.2 700

94.8 5.48 570.2 701

93.63 4.96 546.1 702

96.7 4.7 452.3 703

85.6 4.96 468.2 704

78.36 3.14 359.1 705

47.4 3.9 367.1 706

69.72 4.28 385.2 707

34.86 4.96 393.2 708

37.54 4.91 449.2 709

81.57 4.46 483.1 710

55.98 5.12 491.1 711

73.74 3.09 441.2 712

40.19 2.85 449.2 713

90.07 3.18 426.2 714

74.98 3.84 434.2 715

78.14 4.24 397.2 716

39.87 4.92 405.2 717

57.34 4.45 477.2 718

37.75 5.01 485.1 719

70.3 5.2 412.1 720

70.7 5.0 386.1 721

61.9 6.3 600.3 722

49.3 6.1 538.4 723

65.0 5.1 412.2 724

44.3 4.9 386.2 725

49.2 6.2 600.3 726

37.5 6.0 538.4 727

87.1 5.1 468.1 728

84.4 4.9 442.1 729

82.3 6.2 656.3 730

93.8 4.7 406.3 731

80.7 4.6 380.3 732

84.1 5.9 594.3 733

67.9 4.7 462.1 734

66.9 4.6 436.1 735

56.8 5.9 650.2 736

88.1 4.3 400.3 737

82.8 4.1 374.3 738

51.4 5.6 588.3 739

77.7 5.1 446.2 740

76.1 4.9 420.2 741

67.1 6.2 634.3 742

88.9 4.7 384.3 743

79.3 4.5 358.3 744

65.1 5.9 572.4 745

80.0 4.0 398.3 746

76.9 3.8 372.3 747

42.7 5.8 586.4 748

64.6 4.4 483.3 749

87.4 5.3 409.3 750

71.0 5.1 383.3 751

59.8 6.7 597.4 752

84.4 5.6 494.3 753

80.1 3.9 398.3 754

63.1 3.7 372.3 755

64.4 4.3 483.3 756

84.6 5.3 409.3 757

59.6 5.0 383.3 758

52.9 6.6 597.4 759

81.6 5.5 494.3 760

75.3 5.3 465.3 761

60.3 5.1 439.3 762

61.8 6.6 653.4 763

74.4 5.6 550.3 764

74.5 3.6 448.2 765

51.3 3.4 422.2 766

58.8 3.9 533.2 767

86.2 4.8 459.3 768

63.2 4.6 433.3 769

60.1 6.2 647.4 770

83.5 5.1 544.2 771

68.1 4.1 432.3 772

63.8 3.9 406.2 773

41.1 5.8 620.4 774

62.8 4.4 517.2 775

85.5 5.4 443.3 776

62.5 5.2 417.3 777

66.0 6.7 631.4 778

87.7 5.6 528.3Pharmacological Study

The compounds of the present invention can and have been tested asregards their affinity for different sub-types of somatostatin receptorsaccording to the procedures described below.

Study of the Affinity for the Sub-types of Human Somatostatin Receptors:

The affinity of a compound of the invention for sub-types of humansomatostatin receptors 1 to 5 (sst₁, sst₂, sst₃, sst₄ and sst₅,respectively) is determined by measurement of the inhibition of the bondof [¹²⁵I-Tyr¹¹]SRIF-14 to transfected CHO-K1 cells.

The gene of the sst₁ receptor of human somatostatin has been cloned inthe form of a genomic fragment. A segment PstI-XmnI of 1.5 Kb containing100 bp of the non transcribed 5′ region, 1.17 Kb of the coding region intotality, and 230 bp of the non transcribed 3′ region is modified by theaddition of the linker BglII. The resulting DNA fragment is subcloned inthe BamHI site of a pCMV-81 in order to produce the expression plasmidin mammals (provided by Dr. Graeme Bell, Univ. Chicago). A cloned cellline expressing in a stable fashion the sst₁ receptor is obtained bytransfection in CHO-K1 cells (ATCC) using the calcium phosphateco-precipitation method. The plasmid pRSV-neo (ATCC) is included asselection marker. Cloned cell lines were selected in an RPMI 1640 mediumcontaining 0.5 mg/ml of G418 (Gibco), followed by circular cloning andmultiplication in culture.

The gene of the sst₂ receptor of human somatostatin, isolated in theform of a genomic fragment of DNA of 1.7 Kb BamHI-HindIII and subclonedin a plasmid vector pGEM3Z (Promega), was provided by Dr. G. Bell (Univ.of Chicago). The expression vector of the mammalian cells is constructedby inserting the BamH1-HindII fragment of 1.7 Kb in endonucleaserestriction sites compatible with the plasmid pCMV5. A cloned cell lineis obtained by transfection in CHO-K1 cells using the calcium phosphateco-precipitation method. The plasmid pRSV-neo is included as selectionmarker.

The sst₃ receptor is isolated as a genomic fragment, and the completecoding sequence is contained in a BamHI/HindIII fragment of 2.4 Kb. Theexpression plasmid in mammals, pCMV-h3, is constructed by insertion ofthe NcoI-HindIII fragment of 2.0 Kb in the EcoR1 site of the vector pCMVafter modification of the terminations and addition of EcoR1 linkers. Acloned cell line expressing in a stable fashion the sst₃ receptor isobtained by transfection in CHO-K1 cells (ATCC) by the calcium phosphateco-precipitation method. The plasmid pRSV-neo (ATCC) is included asselection marker. Cloned cell lines were selected in an RPMI 1640 mediumcontaining 0.5 mg/ml of G418 (Gibco), followed by circular cloning andmultiplication in culture.

The expression plasmid of the human sst₄ receptor, pCMV-HX, was providedby Dr. Graeme Bell (Univ. Chicago). This vector contains the genomicfragment coding for the human sst₄ receptor of 1.4 Kb NheI-NheI, 456 pbof the non transcribed 5′ region, and 200 pb of the non transcribed 3′region, cloned in the XbaI/EcoR1 sites of PCMV-HX. A cloned cell lineexpressing in a stable fashion the sst₄ receptor is obtained bytransfection in CHO-K1 (ATCC) cells by the calcium phosphateco-precipitation method. The plasmid pRSV-neo (ATCC) is included asselection marker. The cloned cell lines were selected in an RPMI 1640medium containing 0.5 mg/ml of G418 (Gibco), followed by circularcloning and multiplication in culture.

The gene corresponding to the human sst₅ receptor, obtained by the PCRmethod using a genomic λ clone as probe, was provided by Dr. Graeme Bell(Univ. Chicago). The resulting PCR fragment of 1.2 Kb contains 21 basepairs of the non transcribed 5′ region, the coding region in totality,and 55 pb of the non transcribed 3′ region. The clone is inserted in anEcoR1 site of the plasmid pBSSK(+). The insert is recovered in the formof a HindIII-XbaI fragment of 1.2 Kb for subcloning in an expressionvector in mammals, pCVM5. A cloned cell lines expressing in a stablefashion the sst₅ receptor is obtained by transfection in CHO-K1 cells(ATCC) by the calcium phosphate co-precipitation method. The plasmidpRSV-neo (ATCC) is included as selection marker. The cloned cell lineswere selected in an RPMI 1640 medium containing 0.5 mg/ml of G418(Gibco), followed by circular cloning and multiplication in culture.

The CHO-K1 cells which express in a stable fashion one of the human sstreceptors are cultured in an RPMI 1640 medium containing 10% of foetalcalf serum and 0.4 mg/ml of geneticin. The cells are collected with EDTAat 0.5 mM and centrifuged at 500 g for approximately 5 minutes atapproximately 4° C. The pellet is resuspended in Tris 50 mM buffermedium at pH 7.4 and centrifuged twice at 500 g for approximately 5minutes at approximately 4° C. The cells are lysed by sonication thencentrifuged at 39000 g for approximately 10 minutes at 4° C. The pelletis resuspended in the same buffer and centrifuged at 50000 g forapproximately 10 minutes at approximately 4° C. and the cell membranesin the pellet obtained are stored at −80° C.

The competitive inhibition tests of the bond with [¹²⁵I-Tyr¹¹]SRIF-14are carried out in duplicate in 96-well polypropylene plates. The cellmembranes (10 μg protein/well) are incubated with [¹²⁵I-Tyr¹¹]SRIF-14(0.05 nM) for approximately 60 min. at approximately 37° C. in a HEPES50 mM buffer (pH 7.4) containing BSA 0.2%, MgCl₂ 5 mM, Trasylol 200KIU/ml, bacitricin 0.02 mg/ml and phenylmethylsulphonyl fluoride 0.02mg/ml.

The bound [¹²⁵I-Tyr¹¹]SRIF-14 is separated from the free[¹²⁵I-Tyr¹¹]SRIF-14 by immediate filtration through GF/C glass fibrefilter plates (Unifilter, Packard) pre-impregnated with 0.1% ofpolyethylenimine (P.E.I.), using a Filtermate 196 (Packard). The filtersare washed with 50 mM HEPES buffer at approximately 0-4° C. forapproximately 4 seconds and their radioactivity is determined using acounter (Packard Top Count).

The specific bond is obtained by subtracting the non-specific bond(determined in the presence of 0.1 μM of SRIF-14) from the total bond.The data relative to the bond are analyzed by computer-aided non-linearregression analysis (MDL) and the values of the inhibition constants(Ki) are determined.

Determination of the agonist or antagonist character of a compound ofthe present invention is carried out using the test described below.

Functional Test Inhibition of Production of Intracellular cAMP:

CHO-K1 cells expressing the sub-types of human somatostatin receptors(SRIF-14) are cultured in 24-well plates in an RPMI 1640 medium with 10%of foetal calf serum and 0.4 mg/ml of geneticin. The medium is changedthe day preceding the experiment.

The cells at a rate of 10⁵ cells/well are washed twice with 0.5 ml ofnew RPMI medium comprising 0.2% BSA completed by 0.5 mM of3-isobutyl-1-methylxanthine (IBMX) and incubated for approximately 5 minat approximately 37° C.

-   the production of cyclic AMP is stimulated by the addition of 1 mM    of forskolin (FSK) for 15-30 minutes at approximately 37° C.-   the inhibitory effect of the somatostatin of an agonist compound is    measured by the simultaneous addition of FSK (1 μM), SRIF-14 (10⁻¹²    M to 10⁻⁶ M) and of the compound to be tested (10⁻¹⁰ M to 10⁻⁵ M).-   the antagonist effect of a compound is measured by the simultaneous    addition of FSK (1 μM), SRIF-14 (1 to 10 nM) and of the compound to    be tested (10⁻¹⁰ M to 10⁻⁵ M).

The reaction medium is eliminated and 200 ml of 0.1 N HCl are added. Thequantity of cAMP is measured by a radioimmunological test (FlashPlateSMP001A kit, New England Nuclear).

Results:

The tests carried out according to the protocols described above havedemonstrated that the products of general formula (I) defined in thepresent Application have a good affinity for at least one of thesub-types of somatostatin receptors, the inhibition constant K₁ beinglower than micromolar for certain exemplified compounds.

1. A compound of the formula

in racemic, enantiomeric form or all combinations of these forms,wherein R₁ is —(CH₂)_(m)-Y-Z₁₁ or —(CH₂)_(m)-Z₁₂, Z₁₁ is (C₁-C₆)alkyl oroptionally substituted aryl, Z₁₂ is bis-phenyl optionally substitutedaryl or -optionally substituted heteroaryl, R₂ is selected from thegroup consisting of —C(Y)NHX₁, —C(O)X₂ and SO₂X₃; R₃ is selected fromthe group consisting of hydrogen, an optionally substituted alkyl,alkenyl and alkynyl, X₁ is selected from the group consisting of(C₁-C₁₅)alkyl, alkenyl, alkynyl, —(CH₂)_(m)-Y-Z₂₁ and —(CH₂)_(p)Z₂₂, Z₂₁is (C₁-C₆)alkyl Z₂₂ is selected from the group consisting ofcyclohexenyl, indanyl, bis-phenyl, (C₃-C₇)cycloalkyl and(C₃-C₇)heterocycloalkyl, aryl and heteroaryl optionally substituted X₂is selected from the group consisting of alkenyl optionally substitutedby phenyl optionally substituted, alkynyl, —(CH₂)_(m)-W-(CH₂)_(q)-Z₂₃and —(CH₂)_(p)-U-Z₂₄ wherein Z₂₃ is (C₁-C₆)alkyl or aryl optionallysubstituted; Z₂₄ is selected from the group consisting of cyclohexenyl,bis-phenyl, (C₃-C₇)cycloalkyl optionally substituted,(C₃-C₇)heterocycloalkyl, cyano, amino, mono and di-alkylamino, aryl andheteroaryl optionally substituted, X₃ is selected from the groupconsisting of (C₁-C₁₀)alkyl, alkenyl optionally substituted by phenyloptionally substituted, —CF₃, and —(CH₂)_(p)Z₂₅, Z₂₅ is aryl optionallysubstituted, Y is oxygen or sulfur, W is oxygen or sulfur or SO₂; U is acovalent bond or oxygen; n is an integer from 0 to 4; m is an integerfrom 1 to 6; p is an integer from 0 to 6; q is an integer from 0 to 2,and their addition salts with pharmaceutically acceptable acids.
 2. Acompound of claim 1 wherein i) the substituents carried by arylrepresented by Z₁₁ and Z₁₂ and heteroaryl represented by Z₁₂ areindependently selected from the group consisting of fluoro, chloro,bromo, iodo, alkyl, alkoxy, alkylthio, —CF₃, —OCF₃, phenyl, phenoxy andaminosulfonyl; iii) the substituents carried by aryl and heteroarylrepresented by Z₂₂ are independently selected from the group consistingof fluoro, chloro, bromo, iodo, alkyl, alkenyl, alkoxy, alkylthio, —CF₃,—OCF₃, nitro, cyano, azido, aminosulfonyl, piperidinosulfonyl, mono- ordi-alkylamino, —C(O)—O-alkyl, —C(O)-alkyl, phenyl, phenoxy, phenylthioand benzyloxy, the phenyl optionally substituted; iv) the substituentscarried by aryl represented by Z₂₃ and Z₂₄, cycloalkyl and heteroarylrepresented by Z₂₄ are selected independently from the group consistingof fluoro, chloro, bromo, iodo, alkyl, alkoxy, alkylthio, —CF₃, —OCF₃,—OCHF₂, —SCF₃, nitro, cyano, azido, hydroxy, —C(O)O-alkyl,—O—C(O)-alkyl, —NH—C(O)-alkyl, alkylsulfonyl, mono- or di-alkylamino,amino, aminoalkyl, pyrrolyl, pyrrolidinyl, phenyl, phenoxy, phenylthio,benzyl and benzyloxy, the aryl is optionally substituted by at least onemember selected from the group consisting of alkyl, CF₃ and halo; v) thesubstituents carried by aryl and heteroaryl represented by Z₂₅ areindependently selected from the group consisting of fluoro, chloro,bromo, iodo, alkyl, alkoxy, —CF₃, —OCF₃, nitro, cyano, —NH—C(O)-alkyl,alkylsulfonyl, amino, mono- and di-alkylamino, phenyl and pyridino; vi)the substituents carried by alkyl represented by R₃ is cyano;
 3. Acompound of claim 1 wherein R₁ is selected from the group consisting of—(CH₂)_(m)-Y-Z₁₁ and —(CH₂)_(m)-Z₁₂, Z₁₁ is (C₁-C₆)alkyl, Z₁₂ isselected from the group consisting of bis-phenyl, optionally substitutedaryl and heteroaryl optionally substituted by at least one memberselected from the group consisting of fluoro, chloro, bromo, iodo, alkyland alkoxy, Y is oxygen, R₂ is selected from the group consisting of—C(Y)NHX₁, —C(O)X₂ and SO₂X₃ wherein X₁ is (C₁-C₁₅)alkyl, or—(CH₂)_(p)Z₂₂, Z₂₂ is selected from the group consisting ofcyclohexenyl, bis-phenyl, (C₃-C₇)cycloalkyl, and(C₃-C₇)heterocycloalkyl, aryl and heteroaryl-unsubstituted orsubstituted by at least one member selected from the group consisting offluoro, chloro, bromo, iodo, alkyl, alkoxy, alkylthio, —CF₃, OCF₃,nitro, cyano, azido, piperidinosulfonyl, —C(O)—O-alkyl, —C(O)-alkyl, orphenyl, X₂ is selected from the group consisting of alkynyl,—(CH₂)_(m)-W-(CH₂)_(q)-U-Z₂₃ and —(CH₂)_(p)-U-Z₂₄, W is SO₂, U is acovalent bond, Z₂₃ is aryl; Z₂₄ is selected from the group consisting ofcyclohexenyl, bis-phenyl, (C₃-C₇)cycloalkyl optionally substituted by anaminoalkyl, aryl and heteroaryl unsubstituted or substituted by at leastone member selected from the group consisting of fluoro, chloro, bromo,iodo, alkyl, alkoxy, —CF₃, —OCF₃, —SCF₃, hydroxy, —O—C(O)-alkyl, mono-or di-alkylamino, amino X₃ is —(CH₂)_(p)Z₂₅, Z₂₅ is aryl optionallysubstituted by at least one member selected from the group consisting ofalkoxy and —CF₃, R₃ is selected from the group consisting of hydrogen,alkyl, alkenyl.
 4. A compound of claim 1 wherein R₁ is [(C₁-C₆)alkyl,]—(CH₂)_(m)-Y-Z₁₁ and —(CH₂)_(m)-Z₁₂, Z₁₁ is (C₁-C₆)alkyl, Z₁₂ isselected from the group consisting of morpholino, bis-phenyl,pyrrolidinyl substituted by oxy, phenyl, piperazinyl, pyridinyl andindolyl, all unsubstituted or substituted by at least one memberselected from the group consisting of bromo, fluoro, chloro, alkyl,alkoxy, —CF₃ and —OCF₃; Y is oxygen.
 5. A compound of claim 1 wherein R₂is selected from the group consisting of —C(Y)NHX₁, —C(O)X₂ and SO₂X₃ X₁is (C₁-C₁₀)alkyl, or —(CH₂)_(p)Z₂₂, Z₂₂ is selected from the groupconsisting of cyclohexyl, cyclohexenyl and bis-phenyl, morpholino,piperidino, and phenyl, naphthyl and furyl unsubstituted or substitutedby at least one member selected from the group consisting of fluoro,chloro, bromo, iodo, alkyl, alkoxy, alkylthio, —CF₃, —OCF₃, nitro,cyano, azido, piperidinosulfonyl, —C(O)—O-alkyl, —C(O)-alkyl,—C(O)-alkyl and phenyl, or Z₂₂ is

X₂ is selected from the group consisting of alkyl, alkynyl,—(CH₂)_(m)-W-(CH₂)_(q)-Z₂₃ and —(CH₂)_(p)Z₂₄, W is SO₂; Z₂₁ is phenyl;Z₂₄ is selected from the group consisting of cyclohexenyl, bis-phenyl,cyclohexyl optionally substituted by an aminoalkyl, and phenyl,naphthyl, benzothienyl, thienyl and indolyl unsubstituted or substitutedby at least one member selected from the group consisting of fluoro,chloro, bromo, iodo, alkyl, alkoxy, —CF₃, —OCF₃, —SCF₃, hydroxy,—O—C(O)-alkyl, —NH—C(O)-alkyl, mono- or di-alkylamino and amino, or X₃is —(CH₂)_(p)Z₂₅, Z₂₅ is phenyl unsubstituted or substituted by at leastone alkoxy or —CF₃.
 6. A compound of claim 1 wherein R₃ is selected fromthe group consisting of hydrogen, alkyl, alkenyl.
 7. A compound of claim1 wherein R₁ is —(CH₂)_(m)Z₁₂ in which m=2 and Z₁₂ is bis-phenyl orindolyl substituted by at least one member selected from the groupconsisting of alkyl and alkoxy.
 8. A compound of claim 1 wherein R₂ is—C(Y)NHX₁ or —C(O)X₂, Y is S; X₁ is phenyl optionally substituted by atleast one azido, X₂ is —(CH₂)_(p)Z₂₄, p is 1, 2 or 3, Z₂₄ is cyclohexyl,or phenyl or benzothienyl optionally substituted by at least one memberselected from the group consisting of fluoro, chloro, bromo, iodo, —CF₃.9. A compound of claim 1 wherein R₃ is hydrogen or methyl.
 10. Apharmaceutical composition having an affinity for somatostatin receptorscomprising an effective amount of a compound of claim 1 and apharmaceutically acceptable carrier.